June 2015
Volume 56, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2015
A novel approach of daunorubicin application on formation of proliferative retinopathy using a porous silicon based, controlled delivery system
Author Affiliations & Notes
  • Lingyun Cheng
    Jacobs Retina Ctr at Shiley Eye Ctr, Univ of California-San Diego, La Jolla, CA
  • Huiyuan Hou
    Jacobs Retina Ctr at Shiley Eye Ctr, Univ of California-San Diego, La Jolla, CA
  • Kristyn Huffman
    Jacobs Retina Ctr at Shiley Eye Ctr, Univ of California-San Diego, La Jolla, CA
  • Sandy Rios
    Jacobs Retina Ctr at Shiley Eye Ctr, Univ of California-San Diego, La Jolla, CA
  • William R Freeman
    Jacobs Retina Ctr at Shiley Eye Ctr, Univ of California-San Diego, La Jolla, CA
  • Michael J Sailor
    Chemistry and Biochemistry, University of California San Diego, La Jolla, CA
  • Footnotes
    Commercial Relationships Lingyun Cheng, Spinnaker Biosciences, Inc. (C), Spinnaker Biosciences, Inc. (I); Huiyuan Hou, None; Kristyn Huffman, None; Sandy Rios, None; William Freeman, Spinnaker Biosciences, Inc (C), Spinnaker Biosciences, Inc (I); Michael Sailor, Spinnaker Biosciences, Inc (I)
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 697. doi:
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    • Get Citation

      Lingyun Cheng, Huiyuan Hou, Kristyn Huffman, Sandy Rios, William R Freeman, Michael J Sailor; A novel approach of daunorubicin application on formation of proliferative retinopathy using a porous silicon based, controlled delivery system. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):697.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: Proliferative vitreoretinopathy (PVR) is the most common cause of poor visual outcomes in association with intraocular surgeries and ocular trauma. Among numerous anti-proliferative agents, daunorubicin (DNR) has shown the strongest efficacy. However, the efficacy is limited by a narrow therapeutic window and a very short vitreous half-life. We hypothesize that a sustained drug delivery system can greatly expand the therapeutic window as well as magnitude of clinical efficacy.

Methods: DNR was covalently loaded to oxidized pSi particles; drug loading and loading efficiency was confirmed by FTIR and TGA, respectively. 3mg of DNR-loaded particles were intravitreally injected into 18 pigmented rabbits and pharmacokinetic data was collected up to 84 days for analysis. In addition, 37 rabbits were used for a dose-escalation (1, 3, 6 mg) safety and efficacy study using a primary rabbit RPE cell induced PVR model in a pre-treatment design setting.

Results: SEM revealed the average particle width and length were 15±2μm and 20±5μm, while the average pore size was 95±17nm with average porosity of 69.8±1.11%. DNR loading efficiency to the particles was 108.55±12μg/mg. 84 days of follow-up did not reveal any adverse reaction. Pharmacokinetic analysis demonstrated a rise-then-lingering profile with maximum DNR concentration (178 ng/ml) at day 7 and minimum concentration (29 ng/ml) at the last day (day 84), which was still above therapeutic level. Intravitreal DNR half-life was 29 days and the mean vitreous residence time was 44 days. DNR-loaded pSi particles were dosed 8 to 9 weeks before RPE cell intravitreal challenge; PVR grading was conducted during 4 weeks of follow up. PVR severity score was dose dependent with a significant negative association with dosing (Spearman ρ=-0.25, p=0.0005); all control eyes including empty pSi injection and gas vitrectomy developed severe PVR. PVR with tractional retinal detachment counted for 88% of the control, 63% of the low dose, 14% of the medium dose, and 0% of the high dose group (Cochran-Armitage Trend Test, p<0.0001).

Conclusions: DNR-loaded pSi particles can safely reside in the vitreous for at least 3 months. This pSi based delivery system extended DNR half-life from a few hours to 29 days, and provided a clinical significant inhibition of PVR formation with a dramatically improved therapeutic window.

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