Antitumor activity of poly(ethylene glycol)–camptothecin conjugate: The inhibition of tumor growth in vivo

• Published in: Journal of controlled release Vol. 110; no. 1; pp. 90 - 102
• Main Authors: Yu, Deshan, Peng, Ping, Dharap, Sonia S., Wang, Yang, Mehlig, Mary, Chandna, Pooja, Zhao, Hong, Filpula, David, Yang, Karen, Borowski, Virna, Borchard, Gerrit, Zhang, Zhihua, Minko, Tamara
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 10-12-2005; Elsevier
• Subjects: Animals; Antineoplastic Agents, Phytogenic - pharmacokinetics; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis; bcl-2-Associated X Protein - genetics; bcl-2-Associated X Protein - metabolism; Biological and medical sciences; Biological Availability; Camptothecin; Camptothecin - analogs & derivatives; Camptothecin - chemistry; Camptothecin - pharmacokinetics; Camptothecin - pharmacology; Caspase 9 - genetics; Caspase 9 - metabolism; Cell Line, Tumor; Colon cancer; Colonic Neoplasms - enzymology; Colonic Neoplasms - genetics; Colonic Neoplasms - prevention & control; Enhanced Permeability and Retention effect; Female; General pharmacology; Green Fluorescent Proteins - chemistry; Green Fluorescent Proteins - pharmacology; Half-Life; Humans; Medical sciences; Mice; Mice, Nude; Neoplasm Transplantation; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Poly(ethylene glycol); Polyethylene Glycols - chemistry; Polyethylene Glycols - pharmacokinetics; Polyethylene Glycols - pharmacology; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; RNA, Messenger - metabolism; Tumor xenografts; Tumor xenografts; Camptothecin; Colon cancer; Enhanced Permeability and Retention effect; Poly(ethylene glycol); Apoptosis; Antineoplastic agent; Pharmaceutical technology; Enzyme; DNA topoisomerase; Enzyme inhibitor; Permeability; Malignant tumor; Heterograft; Retention; Colonic disease; Ethylene oxide polymer; In vivo; Alkaloid; Isomerases; Cell death; Digestive diseases; Intestinal disease; Conjugated compound
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2005.09.050

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.