Therapy of Angiogenic Eye Diseases by Novel Drug Targeting Based on Metal Coordination

• Project/Area Number: 12470362
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Ophthalmology
• Research Institution: KYOTO UNIVERSITY
• Principal Investigator: TABATA Yasuhiko Institute for Medical Sciences, Professor, 再生医科学研究所, 教授 (50211371)
• Co-Investigator(Kenkyū-buntansha): OGURA Yuichiro Department of Ophthalmology, Nagoya City University Medical School, Professor, 医学研究科, 教授 (70191963)
• Project Period (FY): 2000 – 2002
• Project Status: Completed (Fiscal Year 2002)
• Budget Amount: ¥14,000,000 (Direct Cost: ¥14,000,000); Fiscal Year 2002: ¥4,800,000 (Direct Cost: ¥4,800,000); Fiscal Year 2001: ¥4,100,000 (Direct Cost: ¥4,100,000); Fiscal Year 2000: ¥5,100,000 (Direct Cost: ¥5,100,000)
• Keywords: metal coordination / targeting / anti-angiogenic effect / age-related macular degeneration / diabetic retinopathy / eye disease therapy / polymer complex / interferon

Research Abstract

Based on the research of last two years, we have found that dextran is the best watersoluble polymer which can be used for drug targeting to the angiogenic site. Diethylenetriamine pentaacetic acid (DTPA) was introduced to the hydroxyl groups of dextran to prepare DTPA-introduced dextran derivatives with chelating residues (DTPA-dex). The ratio of DTPA introduced was controllable by changing the reaction conditions. The DTPA-dex prepared was mixed in an aqueous solution with interferon (IFN) β in the presence of Zn ions to obtain the DTPA-dex-IFN conjugate with Zn^<2+> coordination. Following the intravenous injection of conjugate into a rabbit model of subretinal angiogenesis, the accumulation of IFN in the angiogenic site was evaluated by the conventional ELISA method. Significantly higher IFN amount was detected in the angiogenic site of rabbit retina for the conjugate injection than the free IFN injection. This finding indicates that the dextran conjugation based on Zn^<2+> coordination enables IFN to target to the subretinal angiogenic site of animals. Therapeutic experiments revealed that the intravenous injection of DTPA-dex-IFN conjugate with Zn^<2+> coordination suppressed the progression of subretinal angiogenesis to a significantly greater extent than that of free IFN or the mixture of DTPA-dex without Zn^<2+> ions. It is possible that efficient IFN targeting to the angiogenic site by metal coordinated conjugation with dextran results in superior anti-angiogenic effect of IFN in the subretina. The similar anti-angiogenic effect of DTPA-dex-IFN conjugate with metal coordination was observed for different rabbit models of subretinal angiogenesis

Research Products

• [Publications] Yasukawa, T., Kimura, H., Tabata, Y., Kamizuru, H., Miyamoto, H., Honda, Y., Ogura, Y.: "Targeting of interferon to choroidal neovascularization by use of dextran and metal coordination"Invest. Ophthalmol. Vis. Sci.. 43. 842-848 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Suginoshita, Y., Tabata, Y., Matsumura, T., Toda, Y., Nabeshima, M., Moriasu, F., Ikada, Y., Chiba, T.: "Liver targeting of human interferon-b with pullulan based on metal corrdination"J. Control. Release.. 83(1). 75-88 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Yasukawa, T., Kimura, H., Tabata, Y., Kamizuru, H., Miyamoto, H., Honda, Y., Ogura, Y.: "Targeting of interferon to choroidal neovascularization by use of dextran and metal coordination"Invest Ophtfaalmol. Vis. Sci.. 43. 842-848 (2002)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Suginoshita, Y., Tabata, Y., Matsumura, T., Toda, Y., Nabeshima, M., Moriasu, E., Ikada, Y., Chiba, T.: "Liver targeting of human interferon-βwith pullulan based on metal corrdination"J. Control Release. 83(1). 75-88 (2002)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Yasukawa, T., Kimura, H., Tabata, Y., Kamizuru, H., Miyamoto, H., Honda, Y., Ogura, Y.: "Targeting of interferon to choroidal neovascularization by use of dextran and metal coordination"Invest. Ophthalmol. Vis. Sci.. 43. 842-848 (2002)
• [Publications] Suginoshita, Y., Tabata, Y, Matsumura, T., Toda, Y., Nabeshima, M., Moriasu, F., Ikada, Y, Chiba, T.: "Liver targeting of human interferon-b with pullulan based on metal corrdination"J. Control. Release.. 83(1). 75-88 (2002)
• [Publications] Suginoshita, Y., Tabata, Y., Moriasu, F., Y., Ikada, Chiba, T.: "Liver targeting of interferon-β with a liver affinity polysaccharide based on metal corrodination in mice"Journal of Pharmacology and Experimental Therapeutics. 298(2). 805-811 (2001)
• [Publications] Yasukawa, T., Kimura, H., Tabata, Y., Ogura, Y.: "Biodegradable scleral plugs for vitreoretinal drug delivery"Advanced Drug Delivery Review. 52(1). 25-36 (2001)
• [Publications] Kimura, H., Yasukawa, T., Tabata, Y., Ogura, Y.: "Drug targeting to choroidal neovascularization"Advanced Drug Delivery Review. 52(1). 79-91 (2001)