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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

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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.

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Availability of data and materials

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors thank the veterinary and husbandry staff for their assistance and Fareeha Zulfiqar for administrative support. The authors thank the veterinary and husbandry staff for their assistance and Fareeha Zulfiqar for administrative support.

Funding

This work was supported by the National Institutes of Health (R01EY031041, R01EY026578 and P30EY001765), the Robert H. Smith Family Foundation, a Sybil B. Harrington Special Scholar Award and a departmental grant from Research to Prevent Blindness, the KKESH—WEI Collaborative Research Fund, a Hartwell Foundation Postdoctoral Fellowship, and the Guerrieri Family Research Fund. Drug measurements were conducted by the Analytical Pharmacology Core (APC) of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. The work conducted by the APC was supported by NIH grants P30CA006973 and S10OD020091, as well as grant number UL1TR003098 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH), and the NIH Roadmap for Medical Research.

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Author notes

  1. Yoo Chun Kim and Henry T. Hsueh are contributed equally to this work.

Authors and Affiliations

  1. Center for Nanomedicine At the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA

    Yoo Chun Kim, Henry T. Hsueh, Matthew D. Shin, Hyounkoo Han, Kirby T. Leo, HyeYoung Kwon, Matthew B. Appell, Usha Rai, Patricia Kolodziejski, Charles Eberhart, Ian Pitha, Donald J. Zack, Justin Hanes & Laura M. Ensign

  2. Department of Ophthalmology, Johns Hopkins University School of Medicine, Wilmer Eye Institute, Baltimore, MD, 21287, USA

    Yoo Chun Kim, Matthew D. Shin, Cynthia A. Berlinicke, Hyounkoo Han, Usha Rai, Charles Eberhart, Ian Pitha, Donald J. Zack, Justin Hanes & Laura M. Ensign

  3. Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA

    Henry T. Hsueh, HyeYoung Kwon, Patricia Kolodziejski, Justin Hanes & Laura M. Ensign

  4. The Sidney Kimmel Comprehensive Cancer Center At Johns Hopkins University, Baltimore, MD, 21287, USA

    Nicole M. Anders, Avelina Hemingway, Justin Hanes & Laura M. Ensign

  5. Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA

    Kirby T. Leo, Justin Hanes & Laura M. Ensign

  6. Department of Computational Biology, Bioinformatics, and Genomics, Center for Bioinformatics and Computational Biology, University of Maryland, College Park, MD, 20742, USA

    Renee Ti Chou

  7. Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, MD, 21287, USA

    Matthew B. Appell, Justin Hanes & Laura M. Ensign

  8. Departments of Neuroscience, Molecular Biology and Genetics, and Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA

    Donald J. Zack

  9. Departments Gynecology and Obstetrics and Infectious Diseases, Johns Hopkins University, Baltimore, MD, 21287, USA

    Laura M. Ensign

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  1. Yoo Chun Kim
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Contributions

Conceptualization: L.M.E, J.H., D.J.Z., Y.C.K. Data collection and analysis: H.T.H., M.D.S., C.A.B., H.H., N.M.A., A.H., K.T.L., R.T.C., H.K., M.B.A., U.R., P.K., C.E., I.P. Writing and editing: L.M.E., Y.C.K., H.T.H., N.M.A., I.P., D.J.Z. All the authors read and approved of the final version of the manuscript.

Corresponding author

Correspondence to Laura M. Ensign.

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All institutional and national guidelines for the care and use of laboratory animals were followed.

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All authors give consent for publication.

Competing interests

Y.C.K., L.M.E., H.T.H., and J.H. are inventors on patents/patent applications related to this technology. J.H. and L.M.E. are co-founders of a start-up company planning to develop the eye drop technology for clinical use. DJZ and CAB are inventors on patents related to sunitinib and neuroprotection. Some of these patents have been licensed to Graybug Vision and to Oriole Therapeutics. J.H. is a co-founder and equity owner of Graybug Vision, and both J.H. and Johns Hopkins own company stock. DJZ is a co-founder and equity owner in Oriole Therapeutics. These arrangements have been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. All other authors declare that they have no competing interests.

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Kim, Y.C., Hsueh, H.T., Shin, M.D. et al. 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. and Transl. Res. 12, 826–837 (2022). https://doi.org/10.1007/s13346-021-00987-6

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