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.