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DOI: 10.1055/s-0038-1657629
In Vivo Photoactivation of Caged-Thrombin
Publication History
Received 21 1997
Accepted 07 May 1997
Publication Date:
12 July 2018 (online)
Summary
Aberrant ocular neovascularization is a major cause of blindness in the world. Abnormal blood vessels in the eye may produce corneal opacification, corneal transplant rejection, neovascular glaucoma, vitreous hemorrhage, traction retinal detachment, and subretinal scars from choroidal neovascular membranes (1-5). Light-induced clotting of blood within these abnormal vessels could provide a novel method for the ablation of deleterious neovascularization. Thrombin is a serine proteinase that participates in the final stages of the coagulation cascade. An inhibitor of thrombin, p-Amidinophenyl-(E)-4-diethyl- amino-2-hydroxy-α-methylcinnamate hydrochloride, MeCINN (1), covalently attaches to the active site serine hydroxyl, inhibiting or caging, the enzyme. Photolysis of the caged-thrombin in vitro causes a trans-cis isomerization of MeCINN which leads to regeneration of active enzyme and cleaving of fibrinogen into fibrin (6). Using a rabbit model of corneal neovascularization, we found that light at 366 nm safely and effectively photoactivates intravenous caged-thrombin and produces localized thrombosis in vivo. These results suggest that intra- vascular photoactivation of caged-thrombin could be used to occlude abnormal blood vessels in the human eye.
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References
- 1 Alldredge OC, Krachmer JH. Clinical types of corneal transplant rejection. Arch Ophthalmol 1981; 99: 599-604
- 2 Gutman FA. Evaluation of a patient with central retinal vein occlusion. Ophthalmol 1983; 90: 481-483
- 3 Davis MD. Vitreous contraction in proliferative diabetic retinopathy. Arch Ophthalmol 1965; 74: 741-751
- 4 Bressler NM, Bressler SB, Fine SL. Age-related macular degeneration. Surv Ophthalmol 1988; 32: 375-413
- 5 Folkman J, Klagsbrun M. Angiogenic factors. Science 1987; 235: 442-447
- 6 Blombäck B, Hessel B, Hogg D, Therkildsen L. A two-step fibrinogen-fibrin transition in blood coagulation. Nature 1978; 275: 501-505
- 7 Turner AD, Pizzo SV, Rozakis GW, Porter NA. Photochemical activation of acylated α-thrombin. J Am Chem Soc 1987; 109: 1274-1275
- 8 Turner AD, Pizzo SV, Rozakis G, Porter NA. Photoactivation of irreversibly inhibited serine proteinases. J Am Chem Soc 1988; 110: 244-250
- 9 Porter NA, Bruhnke JD, Koenigs P. Photoregulation of enzymes. In: Bio-organic Photochemistry Volume 2: Biologic Application of Photochemical Switches. Harry Morrison. (ed). John Wiley & Sons, Inc.; New York, NY: 1993. pp 97-241
- 10 Porter NA, Bruhnke JD. Photocoagulation of human plasma: acyl serine proteinase photochemistry. Photochem Photobiology 1990; 51: 37-43
- 11 Hardaway RM. Disseminated intravascular coagulation syndromes. Arch Surg 1961; 83: 64-72
- 12 Zweifach BW, Lipowsky HH. Quantitative studies of microcirculatory structure and function. Circulation Res 1977; 41: 380-390
- 13 Bush K, Durham NC. Duke University. 1996. Thesis.
- 14 Kohner EM, Laatikainen L, Oughton J. The management of central retinal vein occlusion. Ophthalmol 1983; 90: 484-487