Intravitreal crystalline drug delivery for intraocular proliferation diseases
Lingyun Cheng 1*,
Karl Hostetler 2,
Nadya Valiaeva 2,
Ajay Tammewar 3,
William R. Freeman 3,
James Beadle 2,
Dirk-Uwe G. Bartsch 4,
Kathy Aldern 2,
and
Iryna Falkenstein 5
1 Ophthalmology, Jacobs Retina Center at Shiley Eye Center, UCSD, 9415 Campus Point Drive, La Jolla, California, 92037-0946, United States
2 Department of Medicine, VA Healthcare System and UCSD, La Jolla, California, United States
3 Ophthalmology, Jacobs Retina Center at Shiley Eye Center, UCSD, La Jolla, California, United States
4 Ophthalmology/Shiley Eye Center, University of California, San Diego, La Jolla, California, United States
5 Shiley Eye Center, Jacobs Retina Center, University of California, San Diego (UCSD), La Jolla, California, United States
* To whom correspondence should be addressed. E-mail: cheng{at}eyecenter.ucsd.edu.
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Abstract |
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Purpose: A long-lasting, slow release crystalline antiviral drug delivery system was initially reported using ganciclovir and cyclic cidofovir as the prototype compounds. The current study was undertaken to investigate the feasibility of this system applied 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. The injected eyes were monitored with slit lamp, Tonopen, indirect ophthalmoscopy, electroretinography (ERG), and histology after sacrifice. The selected doses were used for efficacy study with the rat CNV model or the rabbit PVR model. Results: The highest non-toxic dose for HDP-P-AraG was 75µg/eye, and was 70µg/eye and 210µg/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 was visible 4 to 5 weeks for HDP-P-AraG, 8 to 10 weeks for HDP-P-5-F-2dUrd, and longer than 14 weeks for HDP-cP-5-F-2dUrd. The treatment study showed HDP-P-AraG led to 33% reduction of rat CNV (p=0.015) and HDP-cP-5-F-2dUrd provided 100% prevention of trauma induced rabbit PVR (p=0.046). The pretreatment study demonstrated a significant protection against intraocular proliferation compared to the 5-FU in a parallel study (p=0.014). Conclusion: Intravitreal injectable lipid prodrugs of AraG and 5-fluoro-2'-deoxyuridine could be long-lasting, slow release antiproliferative compounds to treat unwanted intraocular proliferation.
Key Words:
intravitreal drug delivery, age-related macular degeneration, antiproliferative effects, prodrugs, vitreoretinopathy
