Machine learning-driven multifunctional peptide engineering for sustained ocular drug delivery

Henry T. Hsueh, Renee Ti Chou, Usha Rai, Wathsala Liyanage, Yoo Chun Kim, Matthew B. Appell, Jahnavi Pejavar, Kirby T. Leo, Charlotte Davison, Patricia Kolodziejski, Ann Mozzer, HyeYoung Kwon, Maanasa Sista, Nicole M. Anders, Avelina Hemingway, Sri Vishnu Kiran Rompicharla, Malia Edwards, Ian Pitha, Justin Hanes, Michael P. Cummings () and Laura M. Ensign ()
Additional contact information
Henry T. Hsueh: Johns Hopkins University School of Medicine
Renee Ti Chou: University of Maryland, College Park
Usha Rai: Johns Hopkins University School of Medicine
Wathsala Liyanage: Johns Hopkins University School of Medicine
Yoo Chun Kim: Johns Hopkins University School of Medicine
Matthew B. Appell: Johns Hopkins University School of Medicine
Jahnavi Pejavar: Johns Hopkins University School of Medicine
Kirby T. Leo: Johns Hopkins University School of Medicine
Charlotte Davison: Johns Hopkins University School of Medicine
Patricia Kolodziejski: Johns Hopkins University School of Medicine
Ann Mozzer: Johns Hopkins University School of Medicine
HyeYoung Kwon: Johns Hopkins University School of Medicine
Maanasa Sista: Johns Hopkins University School of Medicine
Nicole M. Anders: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University
Avelina Hemingway: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University
Sri Vishnu Kiran Rompicharla: Johns Hopkins University School of Medicine
Malia Edwards: Johns Hopkins University School of Medicine
Ian Pitha: Johns Hopkins University School of Medicine
Justin Hanes: Johns Hopkins University School of Medicine
Michael P. Cummings: University of Maryland, College Park
Laura M. Ensign: Johns Hopkins University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract Sustained drug delivery strategies have many potential benefits for treating a range of diseases, particularly chronic diseases that require treatment for years. For many chronic ocular diseases, patient adherence to eye drop dosing regimens and the need for frequent intraocular injections are significant barriers to effective disease management. Here, we utilize peptide engineering to impart melanin binding properties to peptide-drug conjugates to act as a sustained-release depot in the eye. We develop a super learning-based methodology to engineer multifunctional peptides that efficiently enter cells, bind to melanin, and have low cytotoxicity. When the lead multifunctional peptide (HR97) is conjugated to brimonidine, an intraocular pressure lowering drug that is prescribed for three times per day topical dosing, intraocular pressure reduction is observed for up to 18 days after a single intracameral injection in rabbits. Further, the cumulative intraocular pressure lowering effect increases ~17-fold compared to free brimonidine injection. Engineered multifunctional peptide-drug conjugates are a promising approach for providing sustained therapeutic delivery in the eye and beyond.

Date: 2023
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DOI: 10.1038/s41467-023-38056-w

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