Local enema treatment to inhibit FOLH1/GCPII as a novel therapy for inflammatory bowel disease.
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.
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.
Abhijit A
AA
Date
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.
Rana
R
Rais
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.
Taarika
T
Babu
The Center for Nanomedicine, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 N Broadway, Baltimore, MD 21231, USA.
Jairo
J
Ortiz
The Center for Nanomedicine, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 N Broadway, Baltimore, MD 21231, USA.
Pranjali
P
Kanvinde
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Ajit G
AG
Thomas
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Sarah C
SC
Zimmermann
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Alexandra J
AJ
Gadiano
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.
Gilad
G
Halpert
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.
Barbara S
BS
Slusher
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.
Laura M
LM
Ensign
D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004733:Enema; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008807:Mice, Inbred BALB C; D009943:Organophosphorus Compounds / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D014302:Trinitrobenzenesulfonic Acid
C402107:2-(phosphonomethyl)pentanedioic acid; D009943:Organophosphorus Compounds; D014302:Trinitrobenzenesulfonic Acid; D043425:Glutamate Carboxypeptidase II
2-PMPA; Colitis; Folate polyglutamate; Hypotonic; N-acetyl-aspartyl glutamate; TNBS