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Targeting of Interferon to Choroidal Neovascularization by Use of Dextran and Metal Coordination

¹ From the University Eye Hospital Leipzig, Leipzig, Germany; the ² Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan; the ³ Department of Ophthalmology, Nagoya City University Medical School, Nagoya, Japan; and the ⁴ Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan.

PURPOSE. Bioactive proteins such as interferon (IFN) have been reported to be combined with water-soluble polymers, such as dextran, through metal coordination, without need for complicated procedures. In the current study, the targeting and inhibitory effects of IFN combined with dextran on experimental choroidal neovascularization (CNV) were studied in vivo.

METHODS. Interferon (IFN)ß was conjugated to dextran, which has metal-chelating, diethylenetriaminepentaacetic acid (DTPA) residues. Based on metal coordination, conjugation of IFNß with DTPA-dextran resulted from simply mixing both substances in an aqueous solution containing Zn²⁺. The effects of IFNß on the proliferation of human umbilical vein endothelial cells (HUVECs) and bovine retinal pigment epithelial cells (BRPECs) were evaluated. To evaluate the activity loss of IFNß by conjugation, the effect of the conjugate on HUVECs was compared with that of free IFNß. Experimental CNV was induced by subretinal injection of gelatin microspheres containing basic fibroblast growth factor in rabbits. The rabbits with CNV were intravenously treated twice weekly with 7.5 million international units (MIU)/kg per day free IFNß (for 4 weeks), with IFNß-DTPA-dextran conjugate containing 7.5 (for 2 weeks) or 0.75 (for 4 weeks) MIU/kg per day IFNß, or with saline. The effects of these substances were evaluated by fluorescein angiography and histology. To observe the accumulation of conjugate, the doses of IFNß in CNV tissues were measured by enzyme-linked immunosorbent assay.

RESULTS. IFNß inhibited the growth of HUVECs and enhanced the proliferation of BRPECs. The conjugate seemed to preserve approximately 44% of IFNß activity. Although both doses of IFNß-DTPA-dextran inhibited progression of CNV in rabbits, longer term administration of a lower dose of IFNß-DTPA-dextran had a sustained inhibitory effect on progression of CNV (P < 0.05). Histologic studies revealed the inhibitory effect of IFNß-DTPA-dextran on progression of CNV. This conjugate prolonged the plasma half-life of IFNß and enabled IFNß to accumulate in the CNV in rabbits.

CONCLUSIONS. In this study, human IFNß was successfully used to target CNV, an enhanced antiangiogenic effect was achieved by combining it with dextran, based on metal coordination. This targeted delivery of IFNß may have potential as a treatment modality for CNV.