In vivo antitumor activity of cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum(II) formulated in long-circulating liposomes
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 phosphatidyle...
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Veröffentlicht in: | Cancer chemotherapy and pharmacology 1996, Vol.37 (5), p.435-444 |
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creator | MORI, A SU-PING WU HAN, I KHOKHAR, A. R PEREZ-SOLER, R LEAF HUANG |
description | 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. |
doi_str_mv | 10.1007/s002800050409 |
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R ; PEREZ-SOLER, R ; LEAF HUANG</creator><creatorcontrib>MORI, A ; SU-PING WU ; HAN, I ; KHOKHAR, A. R ; PEREZ-SOLER, R ; LEAF HUANG</creatorcontrib><description>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.</description><identifier>ISSN: 0344-5704</identifier><identifier>EISSN: 1432-0843</identifier><identifier>DOI: 10.1007/s002800050409</identifier><identifier>PMID: 8599866</identifier><identifier>CODEN: CCPHDZ</identifier><language>eng</language><publisher>Berlin: Springer</publisher><subject>Animals ; Antineoplastic agents ; Antineoplastic Agents - administration & dosage ; Antineoplastic Agents - pharmacokinetics ; Antineoplastic Agents - pharmacology ; Antineoplastic Agents - therapeutic use ; Biological and medical sciences ; Cell Survival - drug effects ; Chemotherapy ; Cholesterol ; Drug Carriers ; Female ; Fibrosarcoma - drug therapy ; Fibrosarcoma - metabolism ; Fibrosarcoma - pathology ; G(M1) Ganglioside ; Liposomes ; Medical sciences ; Mice ; Mice, Inbred C3H ; Neoplasm Transplantation ; Organoplatinum Compounds - administration & dosage ; Organoplatinum Compounds - pharmacokinetics ; Organoplatinum Compounds - pharmacology ; Organoplatinum Compounds - therapeutic use ; Pharmacology. Drug treatments ; Phosphatidylcholines ; Phosphatidylethanolamines ; Platinum - analysis ; Polyethylene Glycols ; Solubility ; Time Factors ; Tissue Distribution</subject><ispartof>Cancer chemotherapy and pharmacology, 1996, Vol.37 (5), p.435-444</ispartof><rights>1996 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,4009,27902,27903,27904</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=2968851$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/8599866$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>MORI, A</creatorcontrib><creatorcontrib>SU-PING WU</creatorcontrib><creatorcontrib>HAN, I</creatorcontrib><creatorcontrib>KHOKHAR, A. R</creatorcontrib><creatorcontrib>PEREZ-SOLER, R</creatorcontrib><creatorcontrib>LEAF HUANG</creatorcontrib><title>In vivo antitumor activity of cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum(II) formulated in long-circulating liposomes</title><title>Cancer chemotherapy and pharmacology</title><addtitle>Cancer Chemother Pharmacol</addtitle><description>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.</description><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents - administration & dosage</subject><subject>Antineoplastic Agents - pharmacokinetics</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Biological and medical sciences</subject><subject>Cell Survival - drug effects</subject><subject>Chemotherapy</subject><subject>Cholesterol</subject><subject>Drug Carriers</subject><subject>Female</subject><subject>Fibrosarcoma - drug therapy</subject><subject>Fibrosarcoma - metabolism</subject><subject>Fibrosarcoma - pathology</subject><subject>G(M1) Ganglioside</subject><subject>Liposomes</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred C3H</subject><subject>Neoplasm Transplantation</subject><subject>Organoplatinum Compounds - administration & dosage</subject><subject>Organoplatinum Compounds - pharmacokinetics</subject><subject>Organoplatinum Compounds - pharmacology</subject><subject>Organoplatinum Compounds - therapeutic use</subject><subject>Pharmacology. Drug treatments</subject><subject>Phosphatidylcholines</subject><subject>Phosphatidylethanolamines</subject><subject>Platinum - analysis</subject><subject>Polyethylene Glycols</subject><subject>Solubility</subject><subject>Time Factors</subject><subject>Tissue Distribution</subject><issn>0344-5704</issn><issn>1432-0843</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1996</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kF1LHDEUhkOx2NX20kshF0UUNjWfm8yliB8LQkHq9XImk2hkJplOMkv3J_ivDXbx4nDgPA8vhxehE0Z_MUr1ZaaUG0qpopI2X9CCScEJNVIcoAUVUhKlqfyGjnJ-rZZkQhyiQ6OaxqxWC_S2jngbtglDLKHMQ5ow2BK2oexw8tiGTNo60aXOWYgJSiJlgpjJ4_KRsCUnXYAhxGR3tk8v7h9Eh8ceSojzcL5eX2CfpmGuB9fhEHGf4jOxYbLzh_OM-zCmnAaXv6OvHvrsfuz3MXq6vflzfU8eft-tr68eyMiFKsQDA8O4VdRCa70zK66ltE3DlG80FYp7LjvVUcOt9i34hjnnwQvodFuJOEZn_3PHKf2dXS6bIWTr-r5-nua80bpZGc1NFU_34twOrtuMUxhg2m323VX-c88hW-h9baXW9anxGmMUE-9k4IA5</recordid><startdate>1996</startdate><enddate>1996</enddate><creator>MORI, A</creator><creator>SU-PING WU</creator><creator>HAN, I</creator><creator>KHOKHAR, A. R</creator><creator>PEREZ-SOLER, R</creator><creator>LEAF HUANG</creator><general>Springer</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>1996</creationdate><title>In vivo antitumor activity of cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum(II) formulated in long-circulating liposomes</title><author>MORI, A ; SU-PING WU ; HAN, I ; KHOKHAR, A. R ; PEREZ-SOLER, R ; LEAF HUANG</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p235t-fa1a812c50cabcfe862744c9915f970352f24d5d082c7fbaf91eefaf3ad7b24d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1996</creationdate><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents - administration & dosage</topic><topic>Antineoplastic Agents - pharmacokinetics</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Biological and medical sciences</topic><topic>Cell Survival - drug effects</topic><topic>Chemotherapy</topic><topic>Cholesterol</topic><topic>Drug Carriers</topic><topic>Female</topic><topic>Fibrosarcoma - drug therapy</topic><topic>Fibrosarcoma - metabolism</topic><topic>Fibrosarcoma - pathology</topic><topic>G(M1) Ganglioside</topic><topic>Liposomes</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred C3H</topic><topic>Neoplasm Transplantation</topic><topic>Organoplatinum Compounds - administration & dosage</topic><topic>Organoplatinum Compounds - pharmacokinetics</topic><topic>Organoplatinum Compounds - pharmacology</topic><topic>Organoplatinum Compounds - therapeutic use</topic><topic>Pharmacology. Drug treatments</topic><topic>Phosphatidylcholines</topic><topic>Phosphatidylethanolamines</topic><topic>Platinum - analysis</topic><topic>Polyethylene Glycols</topic><topic>Solubility</topic><topic>Time Factors</topic><topic>Tissue Distribution</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>MORI, A</creatorcontrib><creatorcontrib>SU-PING WU</creatorcontrib><creatorcontrib>HAN, I</creatorcontrib><creatorcontrib>KHOKHAR, A. R</creatorcontrib><creatorcontrib>PEREZ-SOLER, R</creatorcontrib><creatorcontrib>LEAF HUANG</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Cancer chemotherapy and pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>MORI, A</au><au>SU-PING WU</au><au>HAN, I</au><au>KHOKHAR, A. R</au><au>PEREZ-SOLER, R</au><au>LEAF HUANG</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>In vivo antitumor activity of cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum(II) formulated in long-circulating liposomes</atitle><jtitle>Cancer chemotherapy and pharmacology</jtitle><addtitle>Cancer Chemother Pharmacol</addtitle><date>1996</date><risdate>1996</risdate><volume>37</volume><issue>5</issue><spage>435</spage><epage>444</epage><pages>435-444</pages><issn>0344-5704</issn><eissn>1432-0843</eissn><coden>CCPHDZ</coden><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.</abstract><cop>Berlin</cop><pub>Springer</pub><pmid>8599866</pmid><doi>10.1007/s002800050409</doi><tpages>10</tpages></addata></record> |
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subjects | Animals Antineoplastic agents Antineoplastic Agents - administration & dosage Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Biological and medical sciences Cell Survival - drug effects Chemotherapy Cholesterol Drug Carriers Female Fibrosarcoma - drug therapy Fibrosarcoma - metabolism Fibrosarcoma - pathology G(M1) Ganglioside Liposomes Medical sciences Mice Mice, Inbred C3H Neoplasm Transplantation Organoplatinum Compounds - administration & dosage Organoplatinum Compounds - pharmacokinetics Organoplatinum Compounds - pharmacology Organoplatinum Compounds - therapeutic use Pharmacology. Drug treatments Phosphatidylcholines Phosphatidylethanolamines Platinum - analysis Polyethylene Glycols Solubility Time Factors Tissue Distribution |
title | In vivo antitumor activity of cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum(II) formulated in long-circulating liposomes |
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