Engineered peptide-drug conjugate provides sustained protection of retinal ganglion cells with topical administration in rats

Henry T Hsueh; Renee Ti Chou; Usha Rai; Patricia Kolodziejski; Wathsala Liyanage; Jahnavi Pejavar; Ann Mozzer; Charlotte Davison; Matthew B Appell; Yoo Chun Kim; Kirby T Leo; HyeYoung Kwon; Maanasa Sista; Nicole M Anders; Avelina Hemingway; Sri Vishnu Kiran Rompicharla; Ian Pitha; Donald J Zack; Justin Hanes; Michael P Cummings; Laura M Ensign

doi:10.1016/j.jconrel.2023.08.058

Engineered peptide-drug conjugate provides sustained protection of retinal ganglion cells with topical administration in rats

J Control Release. 2023 Oct:362:371-380. doi: 10.1016/j.jconrel.2023.08.058. Epub 2023 Sep 4.

Authors

Henry T Hsueh¹, Renee Ti Chou², Usha Rai³, Patricia Kolodziejski¹, Wathsala Liyanage³, Jahnavi Pejavar¹, Ann Mozzer³, Charlotte Davison¹, Matthew B Appell⁴, Yoo Chun Kim³, Kirby T Leo⁵, HyeYoung Kwon¹, Maanasa Sista⁶, Nicole M Anders⁷, Avelina Hemingway⁷, Sri Vishnu Kiran Rompicharla³, Ian Pitha³, Donald J Zack⁸, Justin Hanes⁹, Michael P Cummings², Laura M Ensign¹⁰

Affiliations

¹ Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
² Center for Bioinformatics and Computational Biology, University of Maryland, College Park, College Park, MD, USA.
³ Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, MD, USA.
⁵ Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
⁶ Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA.
⁷ The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA.
⁸ Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Departments of Neuroscience, Molecular Biology and Genetics, and Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁹ Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA; Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, MD, USA; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA.
¹⁰ Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA; Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, MD, USA; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA. Electronic address: lensign@jhmi.edu.

Abstract

Effective eye drop delivery systems for treating diseases of the posterior segment have yet to be clinically validated. Further, adherence to eye drop regimens is often problematic due to the difficulty and inconvenience of repetitive dosing. Here, we describe a strategy for topically dosing a peptide-drug conjugate to achieve effective and sustained therapeutic sunitinib concentrations to protect retinal ganglion cells (RGCs) in a rat model of optic nerve injury. We combined two promising delivery technologies, namely, a hypotonic gel-forming eye drop delivery system, and an engineered melanin binding and cell-penetrating peptide that sustains intraocular drug residence time. We found that once daily topical dosing of HR97-SunitiGel provided up to 2 weeks of neuroprotection after the last dose, effectively doubling the therapeutic window observed with SunitiGel. For chronic ocular diseases affecting the posterior segment, the convenience of an eye drop combined with intermittent dosing frequency could result in greater patient adherence, and thus, improved disease management.

MeSH terms

Administration, Ophthalmic
Administration, Topical
Animals
Cell-Penetrating Peptides / administration & dosage
Drug Delivery Systems
Indoles / administration & dosage
Indoles / pharmacokinetics
Male
Melanins / administration & dosage
Neuroprotective Agents / administration & dosage
Neuroprotective Agents / pharmacokinetics
Ophthalmic Solutions* / administration & dosage
Optic Nerve Injuries / drug therapy
Peptides / administration & dosage
Peptides / chemistry
Rats
Rats, Sprague-Dawley
Retinal Ganglion Cells* / drug effects

Substances

Ophthalmic Solutions
Neuroprotective Agents
Cell-Penetrating Peptides
Indoles
Melanins
Peptides

Abstract

MeSH terms

Substances

Grants and funding