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

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/kp 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.

• Authors: A Mori, S P Wu, I Han, A R Khokhar, R Perez-Soler, L Huang
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 37 Issue 5 Pg. 435-44 ( 1996) ISSN: 0344-5704 [Print] Germany
• PMID: 8599866 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Drug Carriers
• Liposomes
• Organoplatinum Compounds
• Phosphatidylcholines
• Phosphatidylethanolamines
• bis-neodecanoato-1,2-diaminocyclohexaneplatinum(II)
• dioleoyl-N-(monomethoxypolyethylene glycol succinyl)phosphatidylethanolamine
• G(M1) Ganglioside
• Polyethylene Glycols
• Platinum
• Cholesterol

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacokinetics, pharmacology, therapeutic use)
• Cell Survival (drug effects)
• Cholesterol
• Drug Carriers
• Female
• Fibrosarcoma (drug therapy, metabolism, pathology)
• G(M1) Ganglioside
• Liposomes
• Mice
• Mice, Inbred C3H
• Neoplasm Transplantation
• Organoplatinum Compounds (administration & dosage, pharmacokinetics, pharmacology, therapeutic use)
• Phosphatidylcholines
• Phosphatidylethanolamines
• Platinum (analysis)
• Polyethylene Glycols
• Solubility
• Time Factors
• Tissue Distribution