title: Antitumor activity of poly(ethylene glycol)-camptothecin conjugate: the inhibition of tumor growth in vivo.
abstract: Antitumor effect of poly(ethylene glycol)-camptothecin conjugate (PEG-CPT) was studied in the nude mouse model of human colon cancer xenografts. The animals were treated intravenously with 15 mg/kg of camptothecin (CPT) or PEG-CPT conjugate at equivalent CPT dose. Antitumor activity, apoptosis induction and caspase-dependent signaling pathways were studied 12, 24, 48 and 96 h after single injection. In addition, pharmacokinetics, tumor distribution and accumulation of PEG polymer labeled with green fluorescence protein (GFP) were studied. The data obtained showed that the conjugation of low molecular weight anticancer drug CPT with low solubility to high molecular weight water-soluble PEG polymer provides several advantages over the native drug. First, the conjugation improves drug pharmacokinetics in the blood and tumor. Second, such conjugation provides passive tumor targeting by the Enhanced Permeability and Retention (EPR) effect, increasing drug concentration in the tumor. Third, the coupling increases the bioavailability of CPT, induces apoptosis in tumor and, therefore, enhances anticancer activity of PEG-CPT. Thus, the use of macromolecular conjugate provided passive tumor targeting of the drug, improved pharmacokinetics and increased the stability of the drug during circulation. It offered better uptake by the targeted tumor cells and substantially enhanced apoptosis and antitumor activity of the conjugated drug in the tumor and decreased apoptosis in liver and kidney as compared with the native drug. All these characteristics make PEG-CPT conjugate an attractive anticancer drug for the effective chemotherapy of solid tumors.
authors.affiliation: Enzon Pharmaceuticals, Inc., Piscataway, NJ 08854, USA.
authors.forename: Deshan
authors.initials: D
authors.lastname: Yu
authors.forename: Ping
authors.initials: P
authors.lastname: Peng
authors.forename: Sonia S
authors.initials: SS
authors.lastname: Dharap
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.forename: Mary
authors.initials: M
authors.lastname: Mehlig
authors.forename: Pooja
authors.initials: P
authors.lastname: Chandna
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.forename: David
authors.initials: D
authors.lastname: Filpula
authors.forename: Karen
authors.initials: K
authors.lastname: Yang
authors.forename: Virna
authors.initials: V
authors.lastname: Borowski
authors.forename: Gerrit
authors.initials: G
authors.lastname: Borchard
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Zhang
authors.forename: Tamara
authors.initials: T
authors.lastname: Minko
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis; D001682:Biological Availability; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D005260:Female; D049452:Green Fluorescent Proteins / Q000737:chemistry / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011092:Polyethylene Glycols / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D051028:bcl-2-Associated X Protein; C516254:poly(ethylene glycol)-camptothecin conjugate; D049452:Green Fluorescent Proteins; D011092:Polyethylene Glycols; D053453:Caspase 9; D002166:Camptothecin