Local enema treatment to inhibit FOLH1/GCPII as a novel therapy for inflammatory bowel disease

Abhijit A Date; Rana Rais; Taarika Babu; Jairo Ortiz; Pranjali Kanvinde; Ajit G Thomas; Sarah C Zimmermann; Alexandra J Gadiano; Gilad Halpert; Barbara S Slusher; Laura M Ensign

doi:10.1016/j.jconrel.2017.01.036

Local enema treatment to inhibit FOLH1/GCPII as a novel therapy for inflammatory bowel disease

J Control Release. 2017 Oct 10:263:132-138. doi: 10.1016/j.jconrel.2017.01.036. Epub 2017 Jan 31.

Authors

Affiliations

¹ The Center for Nanomedicine, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 N Broadway, Baltimore, MD 21231, USA; Department of Ophthalmology, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 N. Broadway, Baltimore, MD 21231, USA.
² Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³ The Center for Nanomedicine, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 N Broadway, Baltimore, MD 21231, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁴ The Center for Nanomedicine, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 N Broadway, Baltimore, MD 21231, USA.
⁵ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁶ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Departments of Psychiatry and Behavioral Sciences, Medicine, and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: bslusher@jhmi.edu.
⁷ The Center for Nanomedicine, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 N Broadway, Baltimore, MD 21231, USA; Department of Ophthalmology, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 N. Broadway, Baltimore, MD 21231, USA; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 N. Charles Street, Baltimore, MD 21218, USA. Electronic address: lensign@jhmi.edu.

Abstract

Here we evaluate the potential for local administration of a small molecule FOLH1/GCPII inhibitor 2-phosphonomethyl pentanedioic acid (2-PMPA) as a novel treatment for inflammatory bowel disease (IBD). We found that FOLH1/GCPII enzyme activity was increased in the colorectal tissues of mice with TNBS-induced colitis, and confirmed that 2-PMPA inhibited FOLH1/GCPII enzyme activity ex vivo. In order to maximize local enema delivery of 2-PMPA, we studied the effect of vehicle tonicity on the absorption of 2-PMPA in the colon. Local administration of 2-PMPA in a hypotonic enema vehicle resulted in increased colorectal tissue absorption at 30min compared to 2-PMPA administered in an isotonic enema vehicle. Furthermore, local delivery of 2-PMPA in hypotonic enema vehicle resulted in prolonged drug concentrations for at least 24h with minimal systemic exposure. Finally, daily treatment with the hypotonic 2-PMPA enema ameliorated macroscopic and microscopic symptoms of IBD in the TNBS-induced colitis mouse model, indicating the potential of FOLH1/GCPII inhibitors for the local treatment of IBD.

Keywords: 2-PMPA; Colitis; Folate polyglutamate; Hypotonic; N-acetyl-aspartyl glutamate; TNBS.

MeSH terms

Animals
Colitis / chemically induced
Colitis / drug therapy*
Colitis / metabolism
Colitis / pathology
Colon / drug effects
Colon / metabolism
Colon / pathology
Enema*
Glutamate Carboxypeptidase II / antagonists & inhibitors*
Glutamate Carboxypeptidase II / metabolism
Inflammatory Bowel Diseases / chemically induced
Inflammatory Bowel Diseases / drug therapy*
Inflammatory Bowel Diseases / metabolism
Inflammatory Bowel Diseases / pathology
Intestinal Mucosa / drug effects
Intestinal Mucosa / metabolism
Intestinal Mucosa / pathology
Male
Mice, Inbred BALB C
Organophosphorus Compounds / administration & dosage*
Organophosphorus Compounds / blood
Organophosphorus Compounds / pharmacokinetics
Organophosphorus Compounds / therapeutic use
Trinitrobenzenesulfonic Acid

Substances

2-(phosphonomethyl)pentanedioic acid
Organophosphorus Compounds
Trinitrobenzenesulfonic Acid
Glutamate Carboxypeptidase II

Abstract

MeSH terms

Substances

Grants and funding