Targeting of tumor necrosis factor to tumor by use of dextran and metal coordination.
Tumor targeting of recombinant human tumor necrosis factor alpha (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 Cu2+ 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 Cu2+ coordination is a promising way to enhance the anti-tumor effect of TNF as a result of its passive tumor targeting.
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Institute for Frontier Medical Sciences, Kyoto University, 53 Kawara-cho Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
Noda
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Matsui
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Ikada
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Y
D000818:Animals; D002614:Chelating Agents / Q000737:chemistry* / Q000493:pharmacokinetics; D003300:Copper / Q000737:chemistry; D003911:Dextrans / Q000737:chemistry* / Q000493:pharmacokinetics; D004337:Drug Carriers; D005260:Female; D005354:Fibrosarcoma / Q000188:drug therapy*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D004369:Pentetic Acid / Q000737:chemistry* / Q000493:pharmacokinetics; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics
D002614:Chelating Agents; D003911:Dextrans; D004337:Drug Carriers; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D003300:Copper; D004369:Pentetic Acid