Improved antitumor activity of cis-Bis-neodecanoato-trans-R,R-1,2-Diaminocyclohexaneplatinum (II) entrapped in long-circulating liposomes

Song Li, Abdul R. Khokhar, Roman Perez-Soler, Leaf Huang

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum (II) (NDDP) has previously been formulated in conventional liposomes and shown to be nonnephrotoxic in humans, not cross-resistant with cisplatin in different in vitro and in vivo systems, and more active than cisplatin against murine models of experimental liver metastasis. The activity was attributed to the avid uptake of liposomes by the liver. To extend to the treatment of solid tumors outside the liver, NDDP was formulated, in this study, in long-circulating liposomes composed of egg phosphatidylcholine (PC), cholesterol (Chol) and polyethyleneglycol conjugated to phosphatidylethanolamine (PEG-PE). In vitro, PC/ChoI/NDDP liposomes were barely toxic to murine melanoma cells B16-F0 (IC50 = 195.6 μM) as evaluated by tetrazolium dye colorimetric assay. Inclusion of PEG3000-PE into PC/Chol/NDDP liposomes significantly enhanced their cytotoxicity to a level that was comparable to that of DMPC/DMPG/NDDP liposomes (7.3 vs. 7.9 μM). Biodistribution study indicated that PC/Chol/PEG3000-PE/NDDP liposomes could preferentially localize in s.c. melanoma in C57BL/6 mice. PC/Chol/PEG3000-PE/NDDP liposomes were much more efficient in inhibiting tumor growth in vivo than free cisplatin, free NDDP or NDDP formulated in liposomes of other lipid composition. Compared with cisplatin, the in vivo toxicities of PC/Chol/PEG3000-PE/NDDP liposomes were also significantly reduced. Furthermore, if the tumor was treated with local hyperthermia after injection of PC/Chol/PEG3000-PE/NDDP liposomes, the tumor uptake of liposomes increased by 60%. The tumor inhibitory effect of PC/Chol/PEG3000-PE/NDDP was also significantly improved when combined with local hyperthermia.

Original languageEnglish (US)
Pages (from-to)611-617
Number of pages7
JournalOncology Research
Volume7
Issue number12
StatePublished - 1995
Externally publishedYes

Fingerprint

Liposomes
Phosphatidylcholines
Cholesterol
Cisplatin
Induced Hyperthermia
Neoplasms
bis-neodecanoato-1,2-diaminocyclohexaneplatinum(II)
Liver
Dimyristoylphosphatidylcholine
Experimental Melanomas
Poisons
Inbred C57BL Mouse
Inhibitory Concentration 50
Ovum
Melanoma
Theoretical Models
Coloring Agents
Neoplasm Metastasis
Lipids
Injections

Keywords

  • drug-targeting
  • hyperthermia
  • liposomes
  • long-circulating liposomes
  • melanoma
  • NDDP

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Improved antitumor activity of cis-Bis-neodecanoato-trans-R,R-1,2-Diaminocyclohexaneplatinum (II) entrapped in long-circulating liposomes. / Li, Song; Khokhar, Abdul R.; Perez-Soler, Roman; Huang, Leaf.

In: Oncology Research, Vol. 7, No. 12, 1995, p. 611-617.

Research output: Contribution to journalArticle

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abstract = "Cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum (II) (NDDP) has previously been formulated in conventional liposomes and shown to be nonnephrotoxic in humans, not cross-resistant with cisplatin in different in vitro and in vivo systems, and more active than cisplatin against murine models of experimental liver metastasis. The activity was attributed to the avid uptake of liposomes by the liver. To extend to the treatment of solid tumors outside the liver, NDDP was formulated, in this study, in long-circulating liposomes composed of egg phosphatidylcholine (PC), cholesterol (Chol) and polyethyleneglycol conjugated to phosphatidylethanolamine (PEG-PE). In vitro, PC/ChoI/NDDP liposomes were barely toxic to murine melanoma cells B16-F0 (IC50 = 195.6 μM) as evaluated by tetrazolium dye colorimetric assay. Inclusion of PEG3000-PE into PC/Chol/NDDP liposomes significantly enhanced their cytotoxicity to a level that was comparable to that of DMPC/DMPG/NDDP liposomes (7.3 vs. 7.9 μM). Biodistribution study indicated that PC/Chol/PEG3000-PE/NDDP liposomes could preferentially localize in s.c. melanoma in C57BL/6 mice. PC/Chol/PEG3000-PE/NDDP liposomes were much more efficient in inhibiting tumor growth in vivo than free cisplatin, free NDDP or NDDP formulated in liposomes of other lipid composition. Compared with cisplatin, the in vivo toxicities of PC/Chol/PEG3000-PE/NDDP liposomes were also significantly reduced. Furthermore, if the tumor was treated with local hyperthermia after injection of PC/Chol/PEG3000-PE/NDDP liposomes, the tumor uptake of liposomes increased by 60{\%}. The tumor inhibitory effect of PC/Chol/PEG3000-PE/NDDP was also significantly improved when combined with local hyperthermia.",
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