A hypotonic gel-forming eye drop provides enhanced intraocular delivery of a kinase inhibitor with melanin-binding properties for sustained protection of retinal ganglion cells

Yoo Chun Kim; Henry T Hsueh; Matthew D Shin; Cynthia A Berlinicke; Hyounkoo Han; Nicole M Anders; Avelina Hemingway; Kirby T Leo; Renee Ti Chou; HyeYoung Kwon; Matthew B Appell; Usha Rai; Patricia Kolodziejski; Charles Eberhart; Ian Pitha; Donald J Zack; Justin Hanes; Laura M Ensign

doi:10.1007/s13346-021-00987-6

A hypotonic gel-forming eye drop provides enhanced intraocular delivery of a kinase inhibitor with melanin-binding properties for sustained protection of retinal ganglion cells

Drug Deliv Transl Res. 2022 Apr;12(4):826-837. doi: 10.1007/s13346-021-00987-6. Epub 2021 Apr 26.

Authors

Yoo Chun Kim^#^{1

2}, Henry T Hsueh^{1

3}, Matthew D Shin^{1

2}, Cynthia A Berlinicke², Hyounkoo Han^{1

2}, Nicole M Anders⁴, Avelina Hemingway⁴, Kirby T Leo^{1

5}, Renee Ti Chou⁶, HyeYoung Kwon^{1

3}, Matthew B Appell^{1

7}, Usha Rai^{1

2}, Patricia Kolodziejski^{1

3}, Charles Eberhart^{1

2}, Ian Pitha^{1

2}, Donald J Zack^{1

2

8}, Justin Hanes^{1

2

3

4

5

7}, Laura M Ensign^{9

10

11

12

13

14

15}

Affiliations

¹ Center for Nanomedicine At the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA.
² Department of Ophthalmology, Johns Hopkins University School of Medicine, Wilmer Eye Institute, Baltimore, MD, 21287, USA.
³ Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA.
⁴ The Sidney Kimmel Comprehensive Cancer Center At Johns Hopkins University, Baltimore, MD, 21287, USA.
⁵ Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA.
⁶ Department of Computational Biology, Bioinformatics, and Genomics, Center for Bioinformatics and Computational Biology, University of Maryland, College Park, MD, 20742, USA.
⁷ Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, MD, 21287, USA.
⁸ Departments of Neuroscience, Molecular Biology and Genetics, and Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
⁹ Center for Nanomedicine At the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA. lensign@jhmi.edu.
¹⁰ Department of Ophthalmology, Johns Hopkins University School of Medicine, Wilmer Eye Institute, Baltimore, MD, 21287, USA. lensign@jhmi.edu.
¹¹ Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA. lensign@jhmi.edu.
¹² The Sidney Kimmel Comprehensive Cancer Center At Johns Hopkins University, Baltimore, MD, 21287, USA. lensign@jhmi.edu.
¹³ Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA. lensign@jhmi.edu.
¹⁴ Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, MD, 21287, USA. lensign@jhmi.edu.
¹⁵ Departments Gynecology and Obstetrics and Infectious Diseases, Johns Hopkins University, Baltimore, MD, 21287, USA. lensign@jhmi.edu.

^# Contributed equally.

Abstract

While eye drops are the most common ocular dosage form, eye drops for treating diseases of the posterior segment (retina, choroid, optic nerve) have yet to be developed. In glaucoma, eye drops are used extensively for delivering intraocular pressure (IOP)-lowering medications to the anterior segment. However, degeneration of retinal ganglion cells (RGCs) in the retina may progress despite significant IOP lowering, suggesting that a complementary neuroprotective therapy would improve glaucoma management. Here, we describe a hypotonic, thermosensitive gel-forming eye drop for effective delivery of sunitinib, a protein kinase inhibitor with activity against the neuroprotective targets dual leucine zipper kinase (DLK) and leucine zipper kinase (LZK), to enhance survival of RGCs after optic nerve injury. Further, binding of sunitinib to melanin in the pigmented cells in the choroid and retinal pigment epithelium (RPE) led to prolonged intraocular residence time, including therapeutically relevant concentrations in the non-pigmented retinal tissue where the RGCs reside. The combination of enhanced intraocular absorption provided by the gel-forming eye drop vehicle and the intrinsic melanin binding properties of sunitinib led to significant protection of RGCs with only once weekly eye drop dosing. For a chronic disease such as glaucoma, an effective once weekly eye drop for neuroprotection could result in greater patient adherence, and thus, greater disease management and improved patient quality of life.

Keywords: Melanin binding; Sustained delivery; Thermosensitive; Topical delivery.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Disease Models, Animal
Glaucoma* / drug therapy
Humans
Intraocular Pressure
Melanins* / metabolism
Ophthalmic Solutions / metabolism
Protein Kinase Inhibitors / pharmacology
Quality of Life
Retinal Ganglion Cells / metabolism
Sunitinib / metabolism
Sunitinib / pharmacology
Sunitinib / therapeutic use

Substances

Melanins
Ophthalmic Solutions
Protein Kinase Inhibitors
Sunitinib

Abstract

Publication types

MeSH terms

Substances

Grants and funding