title: Intravitreal crystalline drug delivery for intraocular proliferation diseases.
abstract: OBJECTIVE
  A long-lasting, slow-release, crystalline antiviral drug delivery system was initially reported using ganciclovir and cyclic cidofovir as the prototype compounds. The present study was undertaken to investigate the feasibility of applying this system to antiproliferative small molecules.
  
  
  METHODS
  The crystalline lipid prodrugs of hexadecyloxypropyl-arabinofuranosylguanine 5'-monophosphate (HDP-P-AraG), hexadecyloxypropyl 5-fluoro-2'-deoxyuridine cyclic 3',5'-monophosphate (HDP-cP-5-F-2dUrd), and hexadecyloxypropyl 5-fluoro-2'-deoxyuridine 5'-monophosphate (HDP-P-5-F-2dUrd) were synthesized from their parent compounds arabinofuranosylguanine (AraG) and 5-fluoro-2'-deoxyuridine (5-F-2dUrd). All three compounds were tested at escalating doses in rabbit eyes. Only one eye of each animal was injected with test compound, and the fellow eye was injected with 5% dextrose as the control. The injected eyes were monitored by slit lamp, a handheld tonometer, indirect ophthalmoscopy, electroretinography (ERG), and histology. The selected doses were used for efficacy study with the rat CNV model or the rabbit PVR model.
  
  
  RESULTS
  The highest nontoxic dose for HDP-P-AraG was 75 microg/eye, and was 70 and 210 microg/eye for HDP-P-5-F-2dUrd and HDP-cP-5-F-2dUrd, respectively. All compounds demonstrated a localized depot of crystalline aggregate in the vitreous with a clear view of vitreous and retina elsewhere. The drug depot of HDP-P-AraG was visible for 4 to 5 weeks; HDP-P-5-F-2dUrd, 8 to 10 weeks; and HDP-cP-5-F-2dUrd longer than 14 weeks. The treatment study showed HDP-P-AraG led to 33% reduction in CNV in the rat (P = 0.015), and HDP-cP-5-F-2dUrd provided 100% prevention of trauma-induced PVR in the rabbit (P = 0.046). The pretreatment study demonstrated a significant protection against intraocular proliferation compared with the 5-FU in a parallel study (P = 0.014).
  
  
  CONCLUSIONS
  The intravitreous injectable lipid prodrugs of AraG and 5-fluoro-2'-deoxyuridine could be long-lasting, slow-release, antiproliferative compounds to treat unwanted intraocular proliferation.
authors.affiliation: Jacobs Retina Center at Shiley Eye Center, University of California, San Diego, La Jolla, California, USA. cheng@eyecenter.ucsd.edu
authors.forename: Lingyun
authors.initials: L
authors.lastname: Cheng
authors.forename: Karl
authors.initials: K
authors.lastname: Hostetler
authors.forename: Nadya
authors.initials: N
authors.lastname: Valiaeva
authors.forename: Ajay
authors.initials: A
authors.lastname: Tammewar
authors.forename: William R
authors.initials: WR
authors.lastname: Freeman
authors.forename: James
authors.initials: J
authors.lastname: Beadle
authors.forename: Dirk-Uwe
authors.initials: DU
authors.lastname: Bartsch
authors.forename: Kathy
authors.initials: K
authors.lastname: Aldern
authors.forename: Iryna
authors.initials: I
authors.lastname: Falkenstein
mesh_terms: D000818:Animals; D001088:Arabinonucleotides / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000633:toxicity; D003460:Crystallization; D003856:Deoxyuracil Nucleotides / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000633:toxicity; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D005451:Fluorescein Angiography; D007267:Injections; D009887:Ophthalmoscopy; D011355:Prodrugs / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity; D011817:Rabbits; D051381:Rats; D011914:Rats, Inbred BN; D012160:Retina / Q000187:drug effects / Q000473:pathology; D015861:Retinal Neovascularization / Q000473:pathology / Q000517:prevention & control*; D014065:Tonometry, Ocular; D018630:Vitreoretinopathy, Proliferative / Q000473:pathology / Q000517:prevention & control*; D014822:Vitreous Body
chemical_list: D001088:Arabinonucleotides; D003856:Deoxyuracil Nucleotides; D011355:Prodrugs; C546831:hexadecyloxypropyl 5'-fluoro-2'-deoxyuridine 5'-monophosphate; C546830:hexadecyloxypropyl 5-fluoro-2'-deoxyuridine cyclic-3',5'-monophosphate; C546829:hexadecyloxypropyl-arabinofuranosylguanine 5'-monophosphate
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