Effective and Sustained Delivery of Hydrophobic Retinoids to Photoreceptors

Overview

Journal Invest Ophthalmol Vis Sci

Specialty Ophthalmology

Date 2010 Jun 25

PMID 20574023

Citations 23

Authors

Peter H Tang

Jie Fan

Patrice W Goletz

Lee Wheless

Rosalie K Crouch

Affiliations

Soon will be listed here.

Abstract

Purpose: Delivery of hydrophobic compounds to the retina/RPE has been challenging. The purpose of this study was to develop an effective method for the sustained delivery of retinoids to rod and cone photoreceptors of young mice lacking a normal supply of 11-cis retinal.

Methods: Solubilized basement membrane matrix (Matrigel; BD Biosciences, San Jose, CA) loaded with 9-cis retinal was administered subcutaneously into Rpe65(-/-) mouse pups for assessment of delivery to rods and cones and to Rpe65(-/-)Rho(-/-) mouse pups for assessment of delivery to cones. Intraperitoneal injections of 9-cis retinal were used for comparison. Cone density and opsin localization were evaluated with immunohistochemistry. Cone opsin protein levels were assayed with immunoblots, and cone function was analyzed by electroretinography (ERG) recordings. Retinoid content was determined by high-performance liquid chromatography analysis of retinal extracts. Pigment levels were quantified in homogenized retinas by absorption spectroscopy before and after light exposure.

Results: Single administration of Matrigel loaded with 9-cis retinal to Rpe65(-/-) mice increased cone densities in all analyzed regions of the retina compared with mice treated using intraperitoneal delivery. Cone opsin levels increased to near wild-type levels. Similar treatment in Rpe65(-/-)Rho(-/-) mice increased b-wave ERG amplitudes significantly, indicating the maintenance of cone function. Matrigel was shown to continuously release 9-cis retinal for periods up to 1 week.

Conclusions: As a method for sustained drug delivery, subcutaneous administration using Matrigel proved more efficacious than intraperitoneal injection for in vivo delivery of retinoids to cone photoreceptors. These experiments are the first to show a sustained delivery of retinoids in mice and suggest a strategy for potential clinical therapeutic development.

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References

Van Hooser J, Aleman T, He Y, Cideciyan A, Kuksa V, Pittler S . Rapid restoration of visual pigment and function with oral retinoid in a mouse model of childhood blindness. Proc Natl Acad Sci U S A. 2000; 97(15):8623-8. PMC: 26998. DOI: 10.1073/pnas.150236297. View

Seeliger M, Grimm C, Stahlberg F, Friedburg C, Jaissle G, Zrenner E . New views on RPE65 deficiency: the rod system is the source of vision in a mouse model of Leber congenital amaurosis. Nat Genet. 2001; 29(1):70-4. DOI: 10.1038/ng712. View

Fan J, Rohrer B, Moiseyev G, Ma J, Crouch R . Isorhodopsin rather than rhodopsin mediates rod function in RPE65 knock-out mice. Proc Natl Acad Sci U S A. 2003; 100(23):13662-7. PMC: 263870. DOI: 10.1073/pnas.2234461100. View

Miao R, Agata J, Chao L, Chao J . Kallistatin is a new inhibitor of angiogenesis and tumor growth. Blood. 2002; 100(9):3245-52. DOI: 10.1182/blood-2002-01-0185. View

Yoshizawa T, WALD G . Pre-lumirhodopsin and the bleaching of visual pigments. Nature. 1963; 197:1279-86. DOI: 10.1038/1971279a0. View

Batten M, Imanishi Y, Tu D, Doan T, Zhu L, Pang J . Pharmacological and rAAV gene therapy rescue of visual functions in a blind mouse model of Leber congenital amaurosis. PLoS Med. 2005; 2(11):e333. PMC: 1274279. DOI: 10.1371/journal.pmed.0020333. View

Hsiue G, Chang R, Wang C, Lee S . Development of in situ thermosensitive drug vehicles for glaucoma therapy. Biomaterials. 2003; 24(13):2423-30. DOI: 10.1016/s0142-9612(03)00035-8. View

ROBERTS W, Palade G . Increased microvascular permeability and endothelial fenestration induced by vascular endothelial growth factor. J Cell Sci. 1995; 108 ( Pt 6):2369-79. DOI: 10.1242/jcs.108.6.2369. View

Rohrer B, Lohr H, Humphries P, Redmond T, Seeliger M, Crouch R . Cone opsin mislocalization in Rpe65-/- mice: a defect that can be corrected by 11-cis retinal. Invest Ophthalmol Vis Sci. 2005; 46(10):3876-82. DOI: 10.1167/iovs.05-0533. View

10.

Lem J, Krasnoperova N, Calvert P, Kosaras B, Cameron D, Nicolo M . Morphological, physiological, and biochemical changes in rhodopsin knockout mice. Proc Natl Acad Sci U S A. 1999; 96(2):736-41. PMC: 15206. DOI: 10.1073/pnas.96.2.736. View

11.

Rohrer B, Goletz P, Znoiko S, Ablonczy Z, Ma J, Redmond T . Correlation of regenerable opsin with rod ERG signal in Rpe65-/- mice during development and aging. Invest Ophthalmol Vis Sci. 2002; 44(1):310-5. DOI: 10.1167/iovs.02-0567. View

12.

Jacobson S, Aleman T, Cideciyan A, Heon E, Golczak M, Beltran W . Human cone photoreceptor dependence on RPE65 isomerase. Proc Natl Acad Sci U S A. 2007; 104(38):15123-8. PMC: 1986623. DOI: 10.1073/pnas.0706367104. View

13.

Bayer A, Cook P, Brodie S, Maag K, Mittag T . Evaluation of different recording parameters to establish a standard for flash electroretinography in rodents. Vision Res. 2001; 41(17):2173-85. DOI: 10.1016/s0042-6989(01)00103-1. View

14.

Fan J, Wu B, Sarna T, Rohrer B, Redmond T, Crouch R . 9-cis Retinal increased in retina of RPE65 knockout mice with decrease in coat pigmentation. Photochem Photobiol. 2006; 82(6):1461-7. DOI: 10.1562/2006-02-02-RA-793. View

15.

Znoiko S, Rohrer B, Lu K, Lohr H, Crouch R, Ma J . Downregulation of cone-specific gene expression and degeneration of cone photoreceptors in the Rpe65-/- mouse at early ages. Invest Ophthalmol Vis Sci. 2005; 46(4):1473-9. DOI: 10.1167/iovs.04-0653. View

16.

Van Hooser J, Liang Y, Maeda T, Kuksa V, Jang G, He Y . Recovery of visual functions in a mouse model of Leber congenital amaurosis. J Biol Chem. 2002; 277(21):19173-82. PMC: 1470660. DOI: 10.1074/jbc.M112384200. View

17.

Redmond T, Yu S, Lee E, Bok D, HAMASAKI D, Chen N . Rpe65 is necessary for production of 11-cis-vitamin A in the retinal visual cycle. Nat Genet. 1998; 20(4):344-51. DOI: 10.1038/3813. View

18.

SAARI J, Garwin G, Van Hooser J, Palczewski K . Reduction of all-trans-retinal limits regeneration of visual pigment in mice. Vision Res. 1998; 38(10):1325-33. DOI: 10.1016/s0042-6989(97)00198-3. View

19.

Applebury M, Antoch M, Baxter L, Chun L, Falk J, Farhangfar F . The murine cone photoreceptor: a single cone type expresses both S and M opsins with retinal spatial patterning. Neuron. 2000; 27(3):513-23. DOI: 10.1016/s0896-6273(00)00062-3. View

20.

Passaniti A, Taylor R, Pili R, Guo Y, Long P, Haney J . A simple, quantitative method for assessing angiogenesis and antiangiogenic agents using reconstituted basement membrane, heparin, and fibroblast growth factor. Lab Invest. 1992; 67(4):519-28. View