title: A novel cytarabine crystalline lipid prodrug: hexadecyloxypropyl cytarabine 3',5'-cyclic monophosphate for proliferative vitreoretinopathy.
abstract: OBJECTIVE
  The objectives of this study were to synthesize and characterize two types of cytarabine (Ara-C) lipid produgs and evaluate the prodrugs for sustained intraocular delivery after administration by intravitreal injection.
  
  
  METHODS
  Hexadecyloxypropyl cytarabine 5'-monophosphate (HDP-P-Ara-C) and hexadecyloxypropyl cytarabine 3',5'-cyclic monophosphate (HDP-cP-Ara-C) were synthesized starting from cytarabine (1-β-D-arabinofuranosylcytosine). Their vitreal clearance profile was simulated using a custom dissolution chamber, in vitro cytotoxicity was evaluated using cell proliferation assays, and in vivo ocular properties in rat and rabbit eyes were assessed using biomicroscopy, indirect ophthalmoscopy, tonometry, electroretinography, and histology.
  
  
  RESULTS
  HDP-P-Ara-C was cleared from the dissolution chamber (flow rate 2 µL/min) within 7 days. In contrast, HDP-cP-Ara-C, a much more insoluble prodrug, was still detectable 36 days after the dissolution process was started. HDP-P-Ara-C had a 50% cytotoxicity concentration of 52±2.6 μM in human retinal pigment epithelium (ARPE-19) and 32±2.2 µM in a rat Müller cell line, rMC-1. The 50% cytotoxicity concentration values for HDP-cP-Ara-C in ARPE-19 and rMC-1 cells were 50 µM and 25 µM, respectively. HDP-P-Ara-C was not detectable 2 weeks after the highest intravitreal dose (228 µg/rat eye) was injected, and no ocular toxicity was found. With HDP-cP-Ara-C, the drug depot was visible for 26 weeks following a single intravitreal injection (800 µg/rabbit eye). For both compounds, the electroretinogram, intraocular pressure, and other toxicity studies were negative except for the highest dose of HDP-cP-Ara-C (800 µg/eye), which had focal toxicity from the direct touch of the retina and decreased dark adapted a-waves and decreased flicker electroretinogram amplitudes (generalized estimating equations, p=0.039 and 0.01).
  
  
  CONCLUSIONS
  The cyclic monophosphate prodrug, HDP-cP-Ara-C, was found to have physiochemical properties better suited for sustained delivery of cytarabine to posterior segments of the eye. These properties included limited aqueous solubility, in vitro antiproliferative activity, and good tolerability after injection into rabbit eyes.
authors.affiliation: Jacobs Retina Center at Shiley Eye Center, University of California, San Diego, La Jolla, CA 92093-0946, USA.
authors.forename: Jae Suk
authors.initials: JS
authors.lastname: Kim
authors.forename: James R
authors.initials: JR
authors.lastname: Beadle
authors.forename: William R
authors.initials: WR
authors.lastname: Freeman
authors.forename: Karl Y
authors.initials: KY
authors.lastname: Hostetler
authors.forename: Kathrin
authors.initials: K
authors.lastname: Hartmann
authors.forename: Nadejda
authors.initials: N
authors.lastname: Valiaeva
authors.forename: Igor
authors.initials: I
authors.lastname: Kozak
authors.forename: Laura
authors.initials: L
authors.lastname: Conner
authors.forename: Julissa
authors.initials: J
authors.lastname: Trahan
authors.forename: Kathy A
authors.initials: KA
authors.lastname: Aldern
authors.forename: Lingyun
authors.initials: L
authors.lastname: Cheng
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000138:chemical synthesis; D001088:Arabinonucleotides / Q000008:administration & dosage* / Q000138:chemical synthesis; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003568:Cytidine Monophosphate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D003692:Delayed-Action Preparations / Q000008:administration & dosage* / Q000138:chemical synthesis; D015194:Diffusion Chambers, Culture; D004596:Electroretinography; D006801:Humans; D058449:Intravitreal Injections; D007700:Kinetics; D009887:Ophthalmoscopy; D011355:Prodrugs / Q000008:administration & dosage* / Q000138:chemical synthesis; D011817:Rabbits; D051381:Rats; D012160:Retina / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012995:Solubility; D018630:Vitreoretinopathy, Proliferative / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014822:Vitreous Body / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
chemical_list: D000964:Antimetabolites, Antineoplastic; D001088:Arabinonucleotides; D003692:Delayed-Action Preparations; D011355:Prodrugs; C576880:hexadecyloxypropyl cytarabine 3',5'-cyclic monophosphate; C576879:hexadecyloxypropyl cytarabine 5'-monophosphate; D003568:Cytidine Monophosphate