Antitumor activity of folate receptor-targeted liposomal doxorubicin in a KB oral carcinoma murine xenograft model

The expression of folate receptor (FR) is amplified in many types of human cancers. Previously, FR-targeted liposomal doxorubicin (f-L-DOX) has been shown to exhibit superior and selective cytotoxicity against FR(+) tumor cells in vitro compared to nontargeted liposomal doxorubicin (L-DOX). This stu...

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Veröffentlicht in:Pharmaceutical research 2003-03, Vol.20 (3), p.417-422
Hauptverfasser: PAN, Xing Q, HUAQING WANG, LEE, Robert J
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description The expression of folate receptor (FR) is amplified in many types of human cancers. Previously, FR-targeted liposomal doxorubicin (f-L-DOX) has been shown to exhibit superior and selective cytotoxicity against FR(+) tumor cells in vitro compared to nontargeted liposomal doxorubicin (L-DOX). This study further investigates f-L-DOX for its antitumor efficacy in vivo using a murine tumor xenograft model. F-L-DOX composed of DSPC/cholesterol/PEG-DSPE/ folate-PEG-DSPE (65:31:3.5:0.5, mole/mole) was prepared by polycarbonate membrane extrusion followed by remote loading of DOX. Athymic mice on a folate-free diet were engrafted with FR(+) KB cells. Two weeks later, these mice were treated with f-L-DOX, L-DOX, or free DOX in a series of six injections (given intraperitoneally on every fourth day at 10 mg/kg DOX) and monitored for tumor growth and animal survival. The plasma clearance profiles of the DOX formulations and the effect of dietary folate on plasma folate concentration were also analyzed. Plasma folate level remained in the physiologic range relative to that in humans. F-L-DOX exhibited an extended systemic circulation time similar to that of L-DOX. Mice that received f-L-DOX showed greater tumor growth inhibition and a 31% higher (p < 0.01) increase in lifespan compared to those that received L-DOX. Meanwhile, free DOX given at the same dose resulted in significant toxicity and was less effective in prolonging animal survival. FR-targeted liposomes are a highly efficacious vehicle for in vivo delivery of anticancer agents and have potential application in the treatment of FR(+) solid tumors.
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Previously, FR-targeted liposomal doxorubicin (f-L-DOX) has been shown to exhibit superior and selective cytotoxicity against FR(+) tumor cells in vitro compared to nontargeted liposomal doxorubicin (L-DOX). This study further investigates f-L-DOX for its antitumor efficacy in vivo using a murine tumor xenograft model. F-L-DOX composed of DSPC/cholesterol/PEG-DSPE/ folate-PEG-DSPE (65:31:3.5:0.5, mole/mole) was prepared by polycarbonate membrane extrusion followed by remote loading of DOX. Athymic mice on a folate-free diet were engrafted with FR(+) KB cells. Two weeks later, these mice were treated with f-L-DOX, L-DOX, or free DOX in a series of six injections (given intraperitoneally on every fourth day at 10 mg/kg DOX) and monitored for tumor growth and animal survival. The plasma clearance profiles of the DOX formulations and the effect of dietary folate on plasma folate concentration were also analyzed. Plasma folate level remained in the physiologic range relative to that in humans. F-L-DOX exhibited an extended systemic circulation time similar to that of L-DOX. Mice that received f-L-DOX showed greater tumor growth inhibition and a 31% higher (p &lt; 0.01) increase in lifespan compared to those that received L-DOX. Meanwhile, free DOX given at the same dose resulted in significant toxicity and was less effective in prolonging animal survival. FR-targeted liposomes are a highly efficacious vehicle for in vivo delivery of anticancer agents and have potential application in the treatment of FR(+) solid tumors.</description><identifier>ISSN: 0724-8741</identifier><identifier>EISSN: 1573-904X</identifier><identifier>DOI: 10.1023/A:1022656105022</identifier><identifier>PMID: 12669962</identifier><identifier>CODEN: PHREEB</identifier><language>eng</language><publisher>New York, NY: Springer</publisher><subject>Animals ; Antineoplastic agents ; Antineoplastic Agents - administration &amp; dosage ; Antineoplastic Agents - pharmacokinetics ; Antineoplastic Agents - pharmacology ; Biological and medical sciences ; Carcinoma, Squamous Cell - drug therapy ; Carrier Proteins - biosynthesis ; Chemotherapy ; Doxorubicin - administration &amp; dosage ; Doxorubicin - pharmacokinetics ; Doxorubicin - pharmacology ; Fluorometry ; Folate Receptors, GPI-Anchored ; Folic Acid - metabolism ; General pharmacology ; Humans ; Injections, Intraperitoneal ; KB Cells ; Liposomes ; Male ; Medical sciences ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Mouth Neoplasms ; Neoplasm Transplantation ; Pharmaceutical technology. Pharmaceutical industry ; Pharmacology. 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Previously, FR-targeted liposomal doxorubicin (f-L-DOX) has been shown to exhibit superior and selective cytotoxicity against FR(+) tumor cells in vitro compared to nontargeted liposomal doxorubicin (L-DOX). This study further investigates f-L-DOX for its antitumor efficacy in vivo using a murine tumor xenograft model. F-L-DOX composed of DSPC/cholesterol/PEG-DSPE/ folate-PEG-DSPE (65:31:3.5:0.5, mole/mole) was prepared by polycarbonate membrane extrusion followed by remote loading of DOX. Athymic mice on a folate-free diet were engrafted with FR(+) KB cells. Two weeks later, these mice were treated with f-L-DOX, L-DOX, or free DOX in a series of six injections (given intraperitoneally on every fourth day at 10 mg/kg DOX) and monitored for tumor growth and animal survival. The plasma clearance profiles of the DOX formulations and the effect of dietary folate on plasma folate concentration were also analyzed. 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Pharmaceutical industry</subject><subject>Pharmacology. 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Previously, FR-targeted liposomal doxorubicin (f-L-DOX) has been shown to exhibit superior and selective cytotoxicity against FR(+) tumor cells in vitro compared to nontargeted liposomal doxorubicin (L-DOX). This study further investigates f-L-DOX for its antitumor efficacy in vivo using a murine tumor xenograft model. F-L-DOX composed of DSPC/cholesterol/PEG-DSPE/ folate-PEG-DSPE (65:31:3.5:0.5, mole/mole) was prepared by polycarbonate membrane extrusion followed by remote loading of DOX. Athymic mice on a folate-free diet were engrafted with FR(+) KB cells. Two weeks later, these mice were treated with f-L-DOX, L-DOX, or free DOX in a series of six injections (given intraperitoneally on every fourth day at 10 mg/kg DOX) and monitored for tumor growth and animal survival. The plasma clearance profiles of the DOX formulations and the effect of dietary folate on plasma folate concentration were also analyzed. Plasma folate level remained in the physiologic range relative to that in humans. F-L-DOX exhibited an extended systemic circulation time similar to that of L-DOX. Mice that received f-L-DOX showed greater tumor growth inhibition and a 31% higher (p &lt; 0.01) increase in lifespan compared to those that received L-DOX. Meanwhile, free DOX given at the same dose resulted in significant toxicity and was less effective in prolonging animal survival. FR-targeted liposomes are a highly efficacious vehicle for in vivo delivery of anticancer agents and have potential application in the treatment of FR(+) solid tumors.</abstract><cop>New York, NY</cop><pub>Springer</pub><pmid>12669962</pmid><doi>10.1023/A:1022656105022</doi><tpages>6</tpages></addata></record>
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source MEDLINE; SpringerNature Journals
subjects Animals
Antineoplastic agents
Antineoplastic Agents - administration & dosage
Antineoplastic Agents - pharmacokinetics
Antineoplastic Agents - pharmacology
Biological and medical sciences
Carcinoma, Squamous Cell - drug therapy
Carrier Proteins - biosynthesis
Chemotherapy
Doxorubicin - administration & dosage
Doxorubicin - pharmacokinetics
Doxorubicin - pharmacology
Fluorometry
Folate Receptors, GPI-Anchored
Folic Acid - metabolism
General pharmacology
Humans
Injections, Intraperitoneal
KB Cells
Liposomes
Male
Medical sciences
Mice
Mice, Inbred BALB C
Mice, Nude
Mouth Neoplasms
Neoplasm Transplantation
Pharmaceutical technology. Pharmaceutical industry
Pharmacology. Drug treatments
Receptors, Cell Surface
Survival Analysis
Time Factors
Xenograft Model Antitumor Assays
title Antitumor activity of folate receptor-targeted liposomal doxorubicin in a KB oral carcinoma murine xenograft model
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