In vivo antitumor activity of cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum(II) formulated in long-circulating liposomes

Atsuhide Mori, Su Ping Wu, Insook Han, Abdul R. Khokhar, Roman Perez-Soler, Leaf Huang

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

A lipophilic cisplatin derivative, cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum(II) (NDDP), was formulated in liposomes composed of phosphatidylcholine (PC) and cholesterol (Chol) additionally containing monosialoganglioside (GM1) or polyethyleneglycol conjugated to phosphatidylethanolamine (PEG-PE). These NDDP-containing long-circulating liposomes were examined for in vivo antitumor activity using the mouse RIF-1 solid tumor as a target residing outside the reticuloendothelial system (RES). Biodistribution studies, using C3H/HeJ mice and 111In-labelled DTPA-SA as a lipid marker, showed that the activity of GM1 and PEG-PE in prolonging the circulation times of liposomes was preserved in the presence of 3.0 mol% of NDDP in the liposome membranes. The high levels of liposomes remaining in the blood for PC/Chol/GM1 and PC/Chol/PEG3000-PE liposomes were associated with high levels of platinum in the blood as determined by atomic absorption spectrophotometry. These NDDP-containing long-circulating liposomes showed approximately a three-fold increase in tumor accumulation as compared to the conventional PC/Chol liposomes. In vitro cytotoxicity studies using RIF-1 tumor cells showed that the presence of PEG-PE, but not GM1, significantly enhanced the cytotoxicity of liposomal NDDP. RIF-1 tumor-bearing C3H/HeJ mice were treated twice with 25 mg/kg NDDP in various liposomal formulations on days 12 and 16 after tumor cell inoculation. A significant reduction in the tumor growth rate was observed when NDDP was formulated in PC/Chol/PEG3000-PE liposomes which support both efficient tumor accumulation and enhanced cytotoxicity of liposomal NDDP. On the other hand, NDDP formulated in PC/Chol/GM1 liposomes, which display only a high tumor accumulation, had no effect on the tumor growth rate. Furthermore, NDDP formulated in dimyristoylphosphatidylglycerol (DMPG)-containing liposomes, exhibiting in vitro cytotoxicity comparable to NDDP formulated in PC/Chol/PEG3000-PE liposomes, but showing poor tumor accumulation, was also not effective. These results indicate a potential effectiveness of NDDP formulated in PEG-PE-containing liposomes for therapy of tumors in non-RES organs.

Original languageEnglish (US)
Pages (from-to)435-444
Number of pages10
JournalCancer Chemotherapy and Pharmacology
Volume37
Issue number5
DOIs
Publication statusPublished - Jan 1 1996
Externally publishedYes

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Keywords

  • Drug delivery
  • Lipophilic cisplatin
  • Long-circulating liposomes

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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