title: A Novel Approach of Daunorubicin Application on Formation of Proliferative Retinopathy Using a Porous Silicon Controlled Delivery System: Pharmacodynamics.
abstract: OBJECTIVE
  Proliferative vitreoretinopathy (PVR) is the most common cause of poor visual outcomes in association with retinal detachment surgeries and ocular trauma. Daunorubicin (DNR) has shown the strongest efficacy in proliferation inhibition in vitro. However, clinical studies have shown only mild effect owing to limitations of narrow therapeutic window and short vitreous half-life.
  
  
  METHODS
  Three milligrams of DNR-loaded particles were intravitreally injected into 18 pigmented rabbits, and vitreous samples were collected up to 84 days for analysis. Thirty-seven rabbits were used for a dose-escalation (1, 3, 6 mg) safety and efficacy study in a rabbit PVR model using a pretreatment design.
  
  
  RESULTS
  Loading efficiency of DNR was 108.55 ± 12 μg per 1 mg particles. Eighty-four days of follow-up did not reveal any adverse reaction. Pharmacokinetic analysis demonstrated a vitreous half-life of 29 days with a maximum DNR concentration of 178 ng/mL and a minimum concentration of 29 ng/mL at day 84. Daunorubicin-loaded porous silicon (pSi) particles were dosed 8 to 9 weeks before PVR induction, and PVR severity score was dose dependent (Spearman ρ = -0.25, P = 0.0005). Proliferative vitreoretinopathy with tractional retinal detachment was 88% in the control group, 63% in the low-dose group, 14% in the medium-dose group, and 0% in the high-dose group (Cochran-Armitage Trend Test, Z = 8.99, ρ = -0.67, P < 0.0001).
  
  
  CONCLUSIONS
  Daunorubicin-loaded pSi particles can safely reside in the vitreous for at least 3 months. The pSi-based delivery expanded the therapeutic window of DNR by a factor of 862 and drove down the minimum effective concentration by a factor of 175.
authors.affiliation: Department of Ophthalmology Jacobs Retina Center at Shiley Eye Institute, University of California San Diego, La Jolla, California, United States.
authors.forename: Huiyuan
authors.initials: H
authors.lastname: Hou
authors.affiliation: Department of Ophthalmology Jacobs Retina Center at Shiley Eye Institute, University of California San Diego, La Jolla, California, United States.
authors.forename: Kristyn
authors.initials: K
authors.lastname: Huffman
authors.affiliation: Department of Ophthalmology Jacobs Retina Center at Shiley Eye Institute, University of California San Diego, La Jolla, California, United States.
authors.forename: Sandy
authors.initials: S
authors.lastname: Rios
authors.affiliation: Department of Ophthalmology Jacobs Retina Center at Shiley Eye Institute, University of California San Diego, La Jolla, California, United States.
authors.forename: William R
authors.initials: WR
authors.lastname: Freeman
authors.affiliation: Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Sailor
authors.affiliation: Department of Ophthalmology Jacobs Retina Center at Shiley Eye Institute, University of California San Diego, La Jolla, California, United States.
authors.forename: Lingyun
authors.initials: L
authors.lastname: Cheng
mesh_terms: D000818:Animals; D003630:Daunorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D016062:Porosity; D011817:Rabbits; D012825:Silicon; D059005:Topoisomerase II Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D018630:Vitreoretinopathy, Proliferative / Q000188:drug therapy* / Q000378:metabolism; D014822:Vitreous Body / Q000378:metabolism*
chemical_list: D059005:Topoisomerase II Inhibitors; D012825:Silicon; D003630:Daunorubicin
references.citation: Invest Ophthalmol Vis Sci. 2000 May;41(6):1523-32
references.pmid: 10798672
references.citation: J Control Release. 2015 Apr 10;203:109-17
references.pmid: 25700623
references.citation: Invest Ophthalmol Vis Sci. 2004 Nov;45(11):4138-44
references.pmid: 15505067
references.citation: Am J Ophthalmol. 1982 May;93(5):565-72
references.pmid: 7081355
references.citation: Graefes Arch Clin Exp Ophthalmol. 1984;221(5):210-3
references.pmid: 6489768
references.citation: Invest Ophthalmol Vis Sci. 1985 May;26(5):719-25
references.pmid: 3997421
references.citation: Exp Eye Res. 1987 Oct;45(4):579-95
references.pmid: 3428386
references.citation: Graefes Arch Clin Exp Ophthalmol. 1991;229(5):464-7
references.pmid: 1937080
references.citation: Invest Ophthalmol Vis Sci. 1992 Jun;33(7):2160-4
references.pmid: 1607226
references.citation: Graefes Arch Clin Exp Ophthalmol. 1993 Feb;231(2):109-14
references.pmid: 8444357
references.citation: J Ocul Pharmacol. 1994 Fall;10(3):561-70
references.pmid: 7836865
references.citation: Curr Eye Res. 1995 Jun;14(6):473-7
references.pmid: 7671629
references.citation: Br J Ophthalmol. 1995 Oct;79(10):874-7
references.pmid: 7488572
references.citation: Br J Ophthalmol. 1995 Oct;79(10):953-60
references.pmid: 7488586
references.citation: Invest Ophthalmol Vis Sci. 1996 Apr;37(5):843-54
references.pmid: 8603869
references.citation: Invest Ophthalmol Vis Sci. 1996 Oct;37(11):2318-25
references.pmid: 8843916
references.citation: Am J Ophthalmol. 1998 Oct;126(4):550-9
references.pmid: 9780100
references.citation: J Fr Ophtalmol. 2004 Nov;27(9 Pt 1):1051-9
references.pmid: 15557870
references.citation: Ophthalmology. 2004 Dec;111(12):2240-5
references.pmid: 15582080
references.citation: Acta Ophthalmol Scand. 2005 Apr;83(2):184-90
references.pmid: 15799730
references.citation: J Am Chem Soc. 2005 Aug 24;127(33):11636-45
references.pmid: 16104739
references.citation: Nat Protoc. 2007;2(1):67-77
references.pmid: 17401340
references.citation: Invest Ophthalmol Vis Sci. 2010 Jan;51(1):474-81
references.pmid: 19696179
references.citation: Biomaterials. 2011 Mar;32(7):1957-66
references.pmid: 21122914
references.citation: Mol Vis. 2011;17:627-37
references.pmid: 21386925
references.citation: Invest Ophthalmol Vis Sci. 2011;52(13):9391-6
references.pmid: 22058340
references.citation: Small. 2012 May 21;8(10):1579-89
references.pmid: 22411702
references.citation: Invest Ophthalmol Vis Sci. 2012 May;53(6):3167-74
references.pmid: 22491400
references.citation: Mediators Inflamm. 2012;2012:815937
references.pmid: 23049173
references.citation: Invest Ophthalmol Vis Sci. 2013 Feb;54(2):1268-79
references.pmid: 23322571
references.citation: Cochrane Database Syst Rev. 2013;1:CD006421
references.pmid: 23440808
references.citation: Mediators Inflamm. 2013;2013:780634
references.pmid: 24191132
references.citation: J Control Release. 2014 Mar 28;178:46-54
references.pmid: 24424270
references.citation: Ophthalmology. 2001 Jul;108(7):1179-83
references.pmid: 11425671