Pharmacokinetics and Efficacy of the Spleen Tyrosine Kinase Inhibitor R406 after Ocular Delivery for Retinoblastoma

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• 作者：Eleanor M. Pritchard (1) (2)
  Elizabeth Stewart (2)
  Fangyi Zhu (1)
  Cori Bradley (2)
  Lyra Griffiths (2)
  Lei Yang (1)
  Praveen Kumar Suryadevara (1)
  Jiakun Zhang (2)
  Burgess B. Freeman III (3)
  R. Kiplin Guy (1)
  Michael A. Dyer (2) (4) (5) (6)
  
• 关键词：Ocular drug delivery ; R406 ; Retinoblastoma ; Spleen tyrosine kinase
• 刊名：Pharmaceutical Research
• 出版年：2014
• 出版时间：November 2014
• 年：2014
• 卷：31
• 期：11
• 页码：3060-3072
• 全文大小：977 KB
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• 作者单位：Eleanor M. Pritchard (1) (2)
  Elizabeth Stewart (2)
  Fangyi Zhu (1)
  Cori Bradley (2)
  Lyra Griffiths (2)
  Lei Yang (1)
  Praveen Kumar Suryadevara (1)
  Jiakun Zhang (2)
  Burgess B. Freeman III (3)
  R. Kiplin Guy (1)
  Michael A. Dyer (2) (4) (5) (6)
  
  1. Department of Chemical Biology and Therapeutics, St. Jude Children鈥檚 Research Hospital, Memphis, Tennessee, USA
  2. Department of Developmental Neurobiology, St. Jude Children鈥檚 Research Hospital, Memphis, Tennessee, USA
  3. Department of Preclinical Pharmacokinetics, St. Jude Children鈥檚 Research Hospital, Memphis, Tennessee, USA
  4. Department of Ophthalmology, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA
  5. Howard Hughes Medical Institute, Chevy Chase, Maryland, USA
  6. Department of Developmental Neurobiology, St Jude Children鈥檚 Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee, 38105, USA
  
• ISSN：1573-904X

文摘

Purpose Retinoblastoma is a childhood cancer of the retina. Clinical trials have shown that local delivery of broad spectrum chemotherapeutic agents is efficacious. Recent studies characterizing the genomic and epigenomic landscape of retinoblastoma identified spleen tyrosine kinase (SYK) as a promising candidate for targeted therapy. The purpose of this study was to conduct preclinical testing of the SYK antagonist R406 to evaluate it as a candidate for retinoblastoma treatment. Methods The efficacy of the SYK antagonist R406 delivered locally in a human orthotopic xenograft mouse model of retinoblastoma was tested. Intraocular exposure of R406 was determined for various routes and formulations. Results There was no evidence of efficacy for subconjunctival. R406. Maximal vitreal concentration was 10-fold lower than the minimal concentration required to kill retinoblastoma cells in vitro. Dosage of R406 subconjunctivally from emulsion or suspension formulations, direct intravitreal injection of the soluble prodrug of R406 (R788), and repeated topical administration of R406 all increased vitreal exposure, but failed to reach the exposure required for retinoblastoma cell death in culture. Conclusion Taken together, these data suggest that R406 is not a viable clinical candidate for the treatment of retinoblastoma. This study highlights the importance of pharmacokinetic testing of molecular targeted retinoblastoma therapeutics.