A novel cytarabine crystalline lipid prodrug: Hexadecyloxypropyl cytarabine 3 %26apos;,5 %26apos;-cyclic monophosphate for proliferative vitreoretinopathy

作者:Kim Jae Suk; Beadle James R; Freeman William R; Hostetler Karl Y; Hartmann Kathrin; Valiaeva Nadejda; Kozak Igor; Conner Laura; Trahan Julissa; Aldern Kathy A; Cheng Lingyun*
来源:Molecular Vision, 2012, 18(197-98): 1907-1917.

摘要

Purpose: 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. %26lt;br%26gt;Methods: Hexadecyloxypropyl cytarabine 5%26apos;-monophosphate (HDP-P-Ara-C) and hexadecyloxypropyl cytarabine 3%26apos;,5%26apos;-cyclic monophosphate (HDP-cP-Ara-C) were synthesized starting from cytarabine (1-beta-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. %26lt;br%26gt;Results: HDP-P-Ara-C was cleared from the dissolution chamber (flow rate 2 mu L/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 mu M in human retinal pigment epithelium (ARPE-19) and 32 +/- 2.2 mu M in a rat Muller cell line, rMC-1. The 50% cytotoxicity concentration values for HDP-cP-Ara-C in ARPE-19 and rMC-1 cells were 50 mu M and 25 mu M, respectively. HDP-P-Ara-C was not detectable 2 weeks after the highest intravitreal dose (228 mu g/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 mu g/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 mu g/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). %26lt;br%26gt;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.

  • 出版日期2012-7-14