{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T06:13:04Z","timestamp":1791267184296,"version":"4.1.0"},"reference-count":60,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,5,1]],"date-time":"2021-05-01T00:00:00Z","timestamp":1619827200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01EY026578"],"award-info":[{"award-number":["R01EY026578"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30EY001765"],"award-info":[{"award-number":["P30EY001765"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30CA006973"],"award-info":[{"award-number":["P30CA006973"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["S10OD020091"],"award-info":[{"award-number":["S10OD020091"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["UL1TR003098"],"award-info":[{"award-number":["UL1TR003098"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001818","name":"Research to Prevent Blindness","doi-asserted-by":"publisher","award":["Sybil B. Harrington Special Scholar Award and a departmental grant"],"award-info":[{"award-number":["Sybil B. Harrington Special Scholar Award and a departmental grant"]}],"id":[{"id":"10.13039\/100001818","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Guerreri Family Research Fund","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"Robert H. Smith Family Foundation","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"Hartwell Foundation Postdoctoral Fellowship","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Glaucoma is the leading cause of irreversible blindness worldwide. Elevated intraocular pressure (IOP) is one of the major risk factors for glaucoma onset and progression, and available pharmaceutical interventions are exclusively targeted at IOP lowering. However, degeneration of retinal ganglion cells (RGCs) may continue to progress despite extensive lowering of IOP. A complementary strategy to IOP reduction is the use of neuroprotective agents that interrupt the process of cell death by mechanisms independent of IOP. Here, we describe an ion complexation approach for formulating microcrystals containing ~50% loading of a protein kinase inhibitor, sunitinib, to enhance survival of RGCs with subconjunctival injection. A single subconjunctival injection of sunitinib-pamoate complex (SPC) microcrystals provided 20 weeks of sustained retina drug levels, leading to neuroprotection in a rat model of optic nerve injury. Furthermore, subconjunctival injection of SPC microcrystals also led to therapeutic effects in a rat model of corneal neovascularization. Importantly, therapeutically relevant retina drug concentrations were achieved with subconjunctival injection of SPC microcrystals in pigs. For a chronic disease such as glaucoma, a formulation that provides sustained therapeutic effects to complement IOP lowering therapies could provide improved disease management and promote patient quality of life.<\/jats:p>","DOI":"10.3390\/pharmaceutics13050647","type":"journal-article","created":{"date-parts":[[2021,5,1]],"date-time":"2021-05-01T21:35:39Z","timestamp":1619904939000},"page":"647","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Ion-Complex Microcrystal Formulation Provides Sustained Delivery of a Multimodal Kinase Inhibitor from the Subconjunctival Space for Protection of Retinal Ganglion Cells"],"prefix":"10.3390","volume":"13","author":[{"given":"Henry T.","family":"Hsueh","sequence":"first","affiliation":[{"name":"Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA"},{"name":"Department of Chemical &amp; Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoo-Chun","family":"Kim","sequence":"additional","affiliation":[{"name":"Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA"},{"name":"Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Pitha","sequence":"additional","affiliation":[{"name":"Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA"},{"name":"Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew D.","family":"Shin","sequence":"additional","affiliation":[{"name":"Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA"},{"name":"Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia A.","family":"Berlinicke","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8755-6938","authenticated-orcid":false,"given":"Renee Ti","family":"Chou","sequence":"additional","affiliation":[{"name":"Department of Computational Biology, Bioinformatics, and Genomics, Center for Bioinformatics and Computational Biology, University of Maryland, College Park, MD 20742, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Kimball","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Schaub","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Quillen","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1717-5862","authenticated-orcid":false,"given":"Kirby T.","family":"Leo","sequence":"additional","affiliation":[{"name":"Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA"},{"name":"Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyounkoo","family":"Han","sequence":"additional","affiliation":[{"name":"Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA"},{"name":"Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Xiao","sequence":"additional","affiliation":[{"name":"Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA"},{"name":"Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youngwook","family":"Kim","sequence":"additional","affiliation":[{"name":"Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA"},{"name":"Department of Biophysics, Johns Hopkins University, Baltimore, MD 21218, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Appell","sequence":"additional","affiliation":[{"name":"Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA"},{"name":"Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Usha","family":"Rai","sequence":"additional","affiliation":[{"name":"Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA"},{"name":"Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6928-7279","authenticated-orcid":false,"given":"HyeYoung","family":"Kwon","sequence":"additional","affiliation":[{"name":"Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA"},{"name":"Department of Chemical &amp; Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Kolodziejski","sequence":"additional","affiliation":[{"name":"Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA"},{"name":"Department of Chemical &amp; Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laolu","family":"Ogunnaike","sequence":"additional","affiliation":[{"name":"Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA"},{"name":"Department of Chemical &amp; Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole M.","family":"Anders","sequence":"additional","affiliation":[{"name":"The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avelina","family":"Hemingway","sequence":"additional","affiliation":[{"name":"The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joan L.","family":"Jefferys","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6617-882X","authenticated-orcid":false,"given":"Abhijit A.","family":"Date","sequence":"additional","affiliation":[{"name":"Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA"},{"name":"Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"Eberhart","sequence":"additional","affiliation":[{"name":"Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA"},{"name":"Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas V.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA"},{"name":"Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harry A.","family":"Quigley","sequence":"additional","affiliation":[{"name":"Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA"},{"name":"Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, 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Baltimore, MD 21218, USA"},{"name":"Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"},{"name":"Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA"},{"name":"Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, MD 21287, USA"},{"name":"The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6949-7911","authenticated-orcid":false,"given":"Laura M.","family":"Ensign","sequence":"additional","affiliation":[{"name":"Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA"},{"name":"Department of Chemical &amp; Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA"},{"name":"Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"},{"name":"Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA"},{"name":"Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, MD 21287, USA"},{"name":"The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA"},{"name":"Departments Gynecology and Obstetrics and Infectious Diseases, Johns Hopkins University, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1136\/bjo.2005.081224","article-title":"The number of people with glaucoma worldwide in 2010 and 2020","volume":"90","author":"Quigley","year":"2006","journal-title":"Br. 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USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1016\/j.neuron.2017.06.008","article-title":"Enhanced Functional Genomic Screening Identifies Novel Mediators of Dual Leucine Zipper Kinase-Dependent Injury Signaling in Neurons","volume":"94","author":"Welsbie","year":"2017","journal-title":"Neuron"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4039","DOI":"10.1073\/pnas.1211074110","article-title":"DLK initiates a transcriptional program that couples apoptotic and regenerative responses to axonal injury","volume":"110","author":"Watkins","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2501","DOI":"10.1167\/iovs.12-9483n","article-title":"Advances in glaucoma treatment and management: Neurotrophic agents","volume":"53","author":"Chader","year":"2012","journal-title":"Investig. Ophthalmol. Vis. 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