title: Biocompatible reverse thermal gel sustains the release of intravitreal bevacizumab in vivo.
abstract: OBJECTIVE
  We assessed the in vivo release profile of bevacizumab from and biocompatibility of poly(ethylene glycol)-poly-(serinol hexamethylene urethane), or ESHU, a thermoresponsive hydrogel administered intravitreally for drug delivery.
  
  
  METHODS
  The technical feasibility of injection was assessed quantitatively via mechanical testing. For in vivo studies, New Zealand White rabbit eyes were injected intravitreally with 0.05 mL of either: ESHU dissolved in 25 mg/mL bevacizumab, ESHU dissolved in PBS, or 25 mg/mL bevacizumab. Clinical examination included IOP measurements and examination with indirect ophthalmoscopy for signs of inflammation. Additionally, eyes were examined histologically following euthanasia. To quantify bevacizumab release, aqueous humor samples were obtained via anterior chamber paracentesis and ELISA was used to determine the concentration of drug weekly. In vitro cytotoxicity testing also was performed using bovine corneal endothelial cells.
  
  
  RESULTS
  The ESHU was injected easily through a 31-gauge needle, was well tolerated in vivo, and caused minimal cell death in vitro when compared to other common materials, such as silicone oil. The long-term presence of the gel did not affect IOP, and there was no evidence of inflammation histologically or through indirect observation. The ESHU sustained the release of bevacizumab for over 9 weeks and maintained a drug concentration that averaged 4.7 times higher than eyes receiving bolus bevacizumab injections.
  
  
  CONCLUSIONS
  To our knowledge, this is the first report demonstrating sustained bevacizumab release in vivo from an intravitreally injected hydrogel formulation, suggesting that this delivery system may be a promising candidate for ocular drug delivery.
authors.affiliation: Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Britta M
authors.initials: BM
authors.lastname: Rauck
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Friberg
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Medina Mendez
authors.forename: Daewon
authors.initials: D
authors.lastname: Park
authors.forename: Veeral
authors.initials: V
authors.lastname: Shah
authors.forename: Richard A
authors.initials: RA
authors.lastname: Bilonick
authors.forename: Yadong
authors.initials: Y
authors.lastname: Wang
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001082:Aqueous Humor / Q000378:metabolism; D000068258:Bevacizumab; D002417:Cattle; D020256:Choroidal Neovascularization / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D003692:Delayed-Action Preparations; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D004797:Enzyme-Linked Immunosorbent Assay; D005240:Feasibility Studies; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000008:administration & dosage*; D058449:Intravitreal Injections; D009887:Ophthalmoscopy; D011817:Rabbits; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D003692:Delayed-Action Preparations; D042461:Vascular Endothelial Growth Factor A; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D000068258:Bevacizumab
keywords: biocompatibility; injectable gel; ocular drug delivery; sustained release; thermally responsive hydrogel