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; Laura M Ensign

doi:10.1038/s41467-023-38056-w

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

Nat Commun. 2023 May 2;14(1):2509. doi: 10.1038/s41467-023-38056-w.

Authors

Henry T Hsueh^#^{1

2}, Renee Ti Chou^#³, Usha Rai^{1

4}, Wathsala Liyanage^{1

4}, Yoo Chun Kim^{1

4}, Matthew B Appell^{1

5}, Jahnavi Pejavar^{1

2}, Kirby T Leo^{1

6}, Charlotte Davison^{1

2}, Patricia Kolodziejski^{1

2}, Ann Mozzer^{1

4}, HyeYoung Kwon^{1

2}, Maanasa Sista^{1

7}, Nicole M Anders⁸, Avelina Hemingway⁸, Sri Vishnu Kiran Rompicharla^{1

4}, Malia Edwards⁴, Ian Pitha^{1

4}, Justin Hanes^{1

2

4

5

6

8}, Michael P Cummings⁹, Laura M Ensign^{10

11

12

13

14

15}

Affiliations

¹ Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
² Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
³ Center for Bioinformatics and Computational Biology, University of Maryland, College Park, College Park, MD, USA.
⁴ Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵ Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, MD, USA.
⁶ Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
⁷ Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA.
⁸ The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA.
⁹ Center for Bioinformatics and Computational Biology, University of Maryland, College Park, College Park, MD, USA. mcummin1@umd.edu.
¹⁰ Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. lensign@jhmi.edu.
¹¹ Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA. lensign@jhmi.edu.
¹² Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. lensign@jhmi.edu.
¹³ Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, MD, USA. lensign@jhmi.edu.
¹⁴ Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA. lensign@jhmi.edu.
¹⁵ The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA. lensign@jhmi.edu.

^# Contributed equally.

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.

Publication types

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

MeSH terms

Animals
Brimonidine Tartrate
Drug Delivery Systems*
Machine Learning
Melanins*
Peptides
Rabbits

Substances

Melanins
Brimonidine Tartrate
Peptides

Abstract

Publication types

MeSH terms

Substances

Grants and funding