Injectable, Drug-Eluting Nanocrystals Prevent Fibrosis and Stricture Formation In Vivo

Ling Li; Rachel L Shapiro; Min Kyung Joo; Aditya Josyula; Henry T Hsueh; Olaya Brewer Gutierrez; Gilad Halpert; Venkata Akshintala; Haiming Chen; Samuel Curtis; Marina Better; Charlotte Davison; Haijie Hu; Jose Antonio Navarro Almario; Steven N Steinway; Kelton Hunt; Rico E Del Sesto; Jessica Izzi; Kevan J Salimian; Laura M Ensign; Florin M Selaru

doi:10.1053/j.gastro.2023.01.006

Injectable, Drug-Eluting Nanocrystals Prevent Fibrosis and Stricture Formation In Vivo

Gastroenterology. 2023 May;164(6):937-952.e13. doi: 10.1053/j.gastro.2023.01.006. Epub 2023 Jan 16.

Authors

Ling Li¹, Rachel L Shapiro², Min Kyung Joo³, Aditya Josyula², Henry T Hsueh², Olaya Brewer Gutierrez¹, Gilad Halpert³, Venkata Akshintala¹, Haiming Chen¹, Samuel Curtis⁴, Marina Better⁴, Charlotte Davison², Haijie Hu¹, Jose Antonio Navarro Almario¹, Steven N Steinway¹, Kelton Hunt⁵, Rico E Del Sesto⁵, Jessica Izzi⁶, Kevan J Salimian⁷, Laura M Ensign⁸, Florin M Selaru⁹

Affiliations

¹ Division of Gastroenterology and Hepatology, School of Medicine, The Johns Hopkins University, Baltimore, Maryland.
² Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland.
³ Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.
⁴ Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
⁵ Department of Chemistry and Biochemistry, Utah Tech University, St George, Utah.
⁶ Department of Molecular and Comparative Pathobiology, Johns Hopkins University, Baltimore, Maryland.
⁷ Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
⁸ Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland; Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Gynecology and Obstetrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Medicine, Division of Infectious Diseases, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, Sidney Kimmel Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: lensign@jhmi.edu.
⁹ Division of Gastroenterology and Hepatology, School of Medicine, The Johns Hopkins University, Baltimore, Maryland; Department of Oncology, Sidney Kimmel Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland; The Institute for Nanobiotechnology, The Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: fselaru1@jhmi.edu.

PMID: 36657529
PMCID: PMC10151160 (available on 2024-05-01)
DOI: 10.1053/j.gastro.2023.01.006

Abstract

Background & aims: Tissue fibrosis results from uncontrolled healing responses leading to excessive mesenchymal cell activation and collagen and other extracellular matrix deposition. In the gastrointestinal tract, fibrosis leads to narrowing of the lumen and stricture formation. A drug treatment to prevent fibrosis and strictures in the gastrointestinal tract would be transformational for patient care. We aimed to develop a stricture treatment with the following characteristics and components: a small molecule with strong antifibrotic effects that is delivered locally at the site of the stricture to ensure correct lesional targeting while protecting the systemic circulation, and that is formulated with sustained-release properties to act throughout the wound healing processes.

Methods: A high-throughput drug screening was performed to identify small molecules with antifibrotic properties. Next, we formulated an antifibrotic small molecule for sustained release and tested its antifibrotic potential in 3 animal models of fibrosis.

Results: Sulconazole, a US Food and Drug Administration-approved drug for fungal infections, was found to have strong antifibrotic properties. Sulconazole was formulated as sulconazole nanocrystals for sustained release. We found that sulconazole nanocrystals provided superior or equivalent fibrosis prevention with less frequent dosing in mouse models of skin and intestinal tissue fibrosis. In a patient-like swine model of bowel stricture, a single injection of sulconazole nanocrystals prevented stricture formation.

Conclusions: The current data lay the foundation for further studies to improve the management of a range of diseases and conditions characterized by tissue fibrosis.

Keywords: Fibrosis; Nanocrystal; Stricture; Sulconazole; Therapies.

Publication types

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

MeSH terms

Animals
Collagen*
Constriction, Pathologic
Delayed-Action Preparations
Extracellular Matrix* / pathology
Fibrosis
Mice
Swine

Substances

Delayed-Action Preparations
Collagen

Abstract

Publication types

MeSH terms

Substances

Grants and funding