Targeting of tumor necrosis factor to tumor by use of dextran and metal coordination

Abstract

Tumor targeting of recombinant human tumor necrosis factor α (TNF) and consequently an enhanced anti-tumor effect were achieved through conjugation with dextran having metal chelating, diethylenetriaminepentaacetic acid (DTPA) residues based on metal coordination. A simple mixing with the DTPA-dextran in an aqueous solution containing Cu 2+ enabled TNF to coordinately conjugate to dextran. Following intravenous (i.v.) injection into tumor-bearing mice, the TNF–DTPA-dextran conjugate caused a significantly higher tumor accumulation of TNF and the longer retention period than free TNF or its mixture with the DTPA-dextran. Intravenous injection of the TNF–DTPA-dextran conjugate suppressed tumor growth to a significantly greater extent than that of free TNF at a lower injection dose. It is concluded that dextran conjugation based on Cu 2+ coordination is a promising way to enhance the anti-tumor effect of TNF as a result of its passive tumor targeting.