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Tsutomu Yasukawa, Hideya Kimura, Yasuhiko Tabata, Hiroshi Kamizuru, Hideki Miyamoto, Yoshihito Honda, Yuichiro Ogura; Targeting of Interferon to Choroidal Neovascularization by Use of Dextran and Metal Coordination. Invest. Ophthalmol. Vis. Sci. 2002;43(3):842-848.
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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
methods. Interferon (IFN)β was conjugated to dextran, which has
metal-chelating, diethylenetriaminepentaacetic acid (DTPA) residues.
Based on metal coordination, conjugation of IFNβ with DTPA-dextran
resulted from simply mixing both substances in an aqueous solution
containing Zn2+. The effects of IFNβ 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 IFNβ by conjugation, the effect of the conjugate on
HUVECs was compared with that of free IFNβ. 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 IFNβ (for 4 weeks), with
IFNβ-DTPA-dextran conjugate containing 7.5 (for 2 weeks) or 0.75 (for
4 weeks) MIU/kg per day IFNβ, or with saline. The effects of these
substances were evaluated by fluorescein angiography and histology. To
observe the accumulation of conjugate, the doses of IFNβ in CNV
tissues were measured by enzyme-linked immunosorbent assay.
results. IFNβ inhibited the growth of HUVECs and enhanced the proliferation of
BRPECs. The conjugate seemed to preserve approximately 44% of IFNβ
activity. Although both doses of IFNβ-DTPA-dextran inhibited
progression of CNV in rabbits, longer term administration of a lower
dose of IFNβ-DTPA-dextran had a sustained inhibitory effect on
progression of CNV (P < 0.05). Histologic studies
revealed the inhibitory effect of IFNβ-DTPA-dextran on progression of
CNV. This conjugate prolonged the plasma half-life of IFNβ and
enabled IFNβ to accumulate in the CNV in rabbits.
conclusions. In this study, human IFNβ 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 IFNβ
may have potential as a treatment modality for
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