ISSN:
1432-0843
Keywords:
Key words Drug delivery
;
Lipophilic cisplatin
;
Long-circulating liposomes
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
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/PEG3000PE 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.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/s002800050409
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