title: Intravitreal toxicology and duration of efficacy of a novel antiviral lipid prodrug of ganciclovir in liposome formulation.
abstract: OBJECTIVE
  To evaluate the intraocular safety and antiviral treatment efficacy of the sustained lipid prodrug of ganciclovir, 1-O-hexadecylpropanediol-3-phospho-ganciclovir (HDP-P-GCV), as an intravitreal injectable drug system for viral retinitis.
  
  
  METHODS
  HDP-P-GCV was synthesized by coupling 1-O-hexadecyl-propanediol-3-phosphate to either free hydroxyl of ganciclovir in pyridine with dicyclohexylcarbodiimide as catalyst. The compound was formulated into liposomes. The antiviral activity was assessed by DNA reduction in vitro, and intraocular safety was assessed by ophthalmoscopy, electrophysiology, and histology after intravitreal injections, with resultant intravitreal concentrations of 0.2, 0.632, 1.12, and 2 mM. The treatment efficacy was evaluated by simultaneous intravitreal injection of HDP-P-GCV and herpes simplex virus type 1 (HSV-1) or by intravitreal injection of HDP-P-GCV at various times before HSV-1 intravitreal inoculation. Retinitis was scored with ophthalmoscopy and compared with controls.
  
  
  RESULTS
  In vitro, the IC50 of HDP-P-GCV against HSV-1 and human cytomegalovirus (HCMV) infected cells was 0.02 and 0.6 microM, respectively. In rabbits in vivo, HDP-P-GCV dispersed evenly and maintained a good vitreous clarity at all doses except 2 mM final intravitreal concentration. Although cataracts were observed in some eyes at the higher doses, they were not observed in eyes with 0.2 mM final intravitreal concentration. No other indications of ocular toxicity were observed. Intravitreal injection of HDP-P-GCV with resultant 0.2 mM intravitreal concentration in the HSV-1 retinitis rabbit model demonstrated a complete protection of the retina with the simultaneous treatment strategy and a 4 (P = 0.03) to 6-(P = 0.058) week significant protection of retina with the pretreatment strategies when compared with ganciclovir or blank liposome controls.
  
  
  CONCLUSIONS
  In the rabbit model of HSV-1 retinitis HDP-P-GCV acts as a long-lasting intravitreal injectable anti-CMV or anti-HSV compound. This self-assembling liposome system could be applicable for many compounds available for intraocular diseases.
authors.affiliation: Shiley Eye Center, University of California, San Diego, La Jolla 92093-0946, USA.
authors.forename: L
authors.initials: L
authors.lastname: Cheng
authors.forename: K Y
authors.initials: KY
authors.lastname: Hostetler
authors.forename: S
authors.initials: S
authors.lastname: Chaidhawangul
authors.forename: M F
authors.initials: MF
authors.lastname: Gardner
authors.forename: J R
authors.initials: JR
authors.lastname: Beadle
authors.forename: K S
authors.initials: KS
authors.lastname: Keefe
authors.forename: G
authors.initials: G
authors.lastname: Bergeron-Lynn
authors.forename: G M
authors.initials: GM
authors.lastname: Severson
authors.forename: K A
authors.initials: KA
authors.lastname: Soules
authors.forename: A J
authors.initials: AJ
authors.lastname: Mueller
authors.forename: W R
authors.initials: WR
authors.lastname: Freeman
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000032:analysis; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000633:toxicity; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000187:drug effects / Q000502:physiology; D004337:Drug Carriers; D004353:Drug Evaluation, Preclinical; D004596:Electroretinography; D015828:Eye Infections, Viral / Q000473:pathology / Q000517:prevention & control* / Q000821:virology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000821:virology; D015774:Ganciclovir / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000633:toxicity; D006561:Herpes Simplex / Q000473:pathology / Q000517:prevention & control* / Q000821:virology; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000276:immunology; D007267:Injections; D008081:Liposomes; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000821:virology; D009887:Ophthalmoscopy; D011355:Prodrugs / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000633:toxicity; D011817:Rabbits; D012173:Retinitis / Q000473:pathology / Q000517:prevention & control* / Q000821:virology; D014822:Vitreous Body / Q000187:drug effects*
chemical_list: C407662:1-O-hexadecyl-propanediol-3-phospho-ganciclovir; D000956:Antigens, Viral; D000998:Antiviral Agents; D004337:Drug Carriers; D008081:Liposomes; D011355:Prodrugs; D015774:Ganciclovir