title: Preliminary study of the effect of FK506 nanospheric-suspension eye drops on rejection of penetrating keratoplasty.
abstract: OBJECTIVE
  The aim of this study was to investigate the effect of a topical FK506 nanospheric suspension in a rat model of penetrating keratoplasty.
  
  
  METHODS
  FK506 nanospheres were prepared by using a biodegradable poly (lactic-co-glycolic acid) copolymer (PLGA). Its distribution in the eye and blood after a single instillation was examined in rabbits. Sprague-Dawley (SD) rats received corneal heterografts and were topically treated with phosphate-buffered saline (PBS), PLGA, FK-506 0.01% (nanospheres), or dexamethasone 0.05% solutions twice a day for 28 days. Rejection index and graft-survival time were recorded and compared between the four groups. Three grafts were collected at different time points for immunohistochemical studies.
  
  
  RESULTS
  In the cornea, the FK-506 concentration reached its peak within 1 h of a single eye-drop instillation and then decreased by half (1667.85 +/- 611.87 ng/g) at 8 h. FK-506 cannot be detected in rabbit blood. There were significant differences in the graft-survival time between the FK-506 nanosphere group (15.09 +/- 4.81 days) and the other three groups [PBS (7.90 +/- 1.20, t = -4.594, P < 0.001), PLGA (8.44 +/- 0.88, t = - 4.074, P = 0.001) and dexamethasone (10.44 +/- 1.42, t = -2.790, P = 0.012)]. The rejected corneas in the FK506 nanosphere group showed significantly fewer CD4, CD8, CD68, CD79, vascular endothelial growth factor, ICAM, and tumor growth factor-beta(1)-positive cells than those in the other groups.
  
  
  CONCLUSIONS
  FK506 0.01% nanospheric-suspension eye drops delayed the occurrence of corneal allograft rejection and prolonged allograft survival time. The FK506 nanospheres may be valuable in suppressing corneal graft rejection.
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Wen-Lei
authors.initials: WL
authors.lastname: Fei
authors.forename: Jia-Qi
authors.initials: JQ
authors.lastname: Chen
authors.forename: Jin
authors.initials: J
authors.lastname: Yuan
authors.forename: Da-Ping
authors.initials: DP
authors.lastname: Quan
authors.forename: Shi-You
authors.initials: SY
authors.lastname: Zhou
mesh_terms: D000818:Animals; D003315:Cornea / Q000378:metabolism; D003907:Dexamethasone / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D066298:In Vitro Techniques; D015948:Keratoplasty, Penetrating; D019344:Lactic Acid / Q000737:chemistry; D054118:Nanospheres / Q000737:chemistry; D009883:Ophthalmic Solutions / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D016559:Tacrolimus / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013997:Time Factors
chemical_list: D007166:Immunosuppressive Agents; D009883:Ophthalmic Solutions; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D003907:Dexamethasone; D016559:Tacrolimus