Sunitinib malate-loaded biodegradable microspheres for the prevention of corneal neovascularization in rats

Jin Yang; Lixia Luo; Yumin Oh; Tuo Meng; Guihong Chai; Shiyu Xia; David Emmert; Bing Wang; Charles G Eberhart; Seulki Lee; Walter J Stark; Laura M Ensign; Justin Hanes; Qingguo Xu

doi:10.1016/j.jconrel.2020.08.019

Sunitinib malate-loaded biodegradable microspheres for the prevention of corneal neovascularization in rats

J Control Release. 2020 Nov 10:327:456-466. doi: 10.1016/j.jconrel.2020.08.019. Epub 2020 Aug 18.

Authors

Jin Yang¹, Lixia Luo², Yumin Oh³, Tuo Meng⁴, Guihong Chai⁴, Shiyu Xia⁵, David Emmert⁶, Bing Wang⁷, Charles G Eberhart⁸, Seulki Lee³, Walter J Stark⁹, Laura M Ensign¹⁰, Justin Hanes¹¹, Qingguo Xu¹²

Affiliations

¹ Department of Ophthalmology, Myopia Key Laboratory of Health PR, Eye & ENT Hospital of Fudan University, Shanghai 200031, China; Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; The Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
² Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; The Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
³ Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; The Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore 21205, MD, USA.
⁴ Departments of Pharmaceutics, Virginia Commonwealth University, Richmond, VA 23298, USA.
⁵ The Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218, USA.
⁶ Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
⁷ Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; The Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Ophthalmology, Fujian Medical University Union Hospital, 29 Xinquan Road, Gulou District, Fuzhou, Fujian Province 350001, China.
⁸ Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; The Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
⁹ Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; The Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
¹⁰ Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; The Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218, USA; Departments of Biomedical Engineering, Pharmacology & Molecular Sciences, Gynecology and Obstetrics, Infectious Diseases, and Oncology, Johns Hopkins University, Baltimore, MD 21231, USA.
¹¹ Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; The Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218, USA; Departments of Biomedical Engineering, Environmental Health Sciences, Oncology, Neurosurgery, and Pharmacology & Molecular Sciences, Johns Hopkins University, Baltimore, MD 21231, USA. Electronic address: hanes@jhmi.edu.
¹² Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; The Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Departments of Pharmaceutics, Virginia Commonwealth University, Richmond, VA 23298, USA; Department of Ophthalmology, Massey Cancer Center, Center for Pharmaceutical Engineering, Institute for Structural Biology, Drug Discovery & Development, Virginia Commonwealth University, Richmond, VA 23298, USA. Electronic address: qxu@vcu.edu.

Abstract

Corneal neovascularization (NV) predisposes patients to compromised corneal transparency and visional acuity. Sunitinib malate (Sunb-malate) targeting against multiple receptor tyrosine kinases, exerts potent antiangiogenesis. However, the rapid clearance of Sunb-malate eye drops administered through topical instillation limits its therapeutic efficacy and poses a challenge for potential patient compliance. Sunb-malate, the water-soluble form of sunitinib, was shown to have higher intraocular penetration through transscleral diffusion following subconjunctival (SCT) injection in comparison to its sunitinib free base formulation. However, it is difficult to load highly water-soluble drugs and achieve sustained drug release. We developed Sunb-malate loaded poly(D,L-lactic-co-glycolic acid) (PLGA) microspheres (Sunb-malate MS) with a particle size of approximately 15 μm and a drug loading of 7 wt%. Sunb-malate MS sustained the drug release for 30 days under the in vitro infinite sink condition. Subconjunctival (SCT) injection of Sunb-malate MS provided a prolonged ocular drug retention and did not cause ocular toxicity at a dose of 150 μg of active agent. Sunb-malate MS following SCT injection more effectively suppressed the suture-induced corneal NV than either Sunb-malate free drug or the placebo MS. Local sustained release of Sunb-malate through the SCT injection of Sunb-malate MS mitigated the proliferation of vascular endothelial cells and the recruitment of mural cells into the cornea. Moreover, the gene upregulation of proangiogenic factors induced by the pathological process was greatly neutralized by SCT injection of Sunb-malate MS. Our findings provide a sustained release platform for local delivery of tyrosine kinase inhibitors to treat corneal NV.

Keywords: Controlled drug release; PLGA; Subconjunctival injection; Trans-scleral delivery; Tyrosine kinase inhibitor.

Publication types

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

MeSH terms

Animals
Corneal Neovascularization* / prevention & control
Drug Liberation
Endothelial Cells
Humans
Microspheres
Rats
Sunitinib

Substances

Sunitinib

Abstract

Publication types

MeSH terms

Substances

Grants and funding