An inflammation-targeting hydrogel for local drug delivery in inflammatory bowel disease.
There is a clinical need for new, more effective treatments for chronic and debilitating inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis. Targeting drugs selectively to the inflamed intestine may improve therapeutic outcomes and minimize systemic toxicity. We report the development of an inflammation-targeting hydrogel (IT-hydrogel) that acts as a drug delivery system to the inflamed colon. Hydrogel microfibers were generated from ascorbyl palmitate, an amphiphile that is generally recognized as safe (GRAS) by the U.S. Food and Drug Administration. IT-hydrogel microfibers loaded with the anti-inflammatory corticosteroid dexamethasone (Dex) were stable, released drug only upon enzymatic digestion, and demonstrated preferential adhesion to inflamed epithelial surfaces in vitro and in two mouse colitis models in vivo. Dex-loaded IT-hydrogel enemas, but not free Dex enemas, administered every other day to mice with colitis resulted in a significant reduction in inflammation and were associated with lower Dex peak serum concentrations and, thus, less systemic drug exposure. Ex vivo analysis of colon tissue samples from patients with ulcerative colitis demonstrated that IT-hydrogel microfibers adhered preferentially to mucosa from inflamed lesions compared with histologically normal sites. The IT-hydrogel drug delivery platform represents a promising approach for targeted enema-based therapies in patients with colonic IBD.
The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Center for Regenerative Therapeutics, Biomedical Research Institute, Brigham and Women's Hospital, Boston, MA 02115, USA. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Sufeng
S
Zhang
Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA 02115, USA. Harvard Medical School, Boston, MA 02115, USA.
Joerg
J
Ermann
The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Center for Regenerative Therapeutics, Biomedical Research Institute, Brigham and Women's Hospital, Boston, MA 02115, USA. Harvard Medical School, Boston, MA 02115, USA.
Marc D
MD
Succi
Center for Regenerative Therapeutics, Biomedical Research Institute, Brigham and Women's Hospital, Boston, MA 02115, USA.
Allen
A
Zhou
Harvard Medical School, Boston, MA 02115, USA. Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Boston, MA 02115, USA.
Matthew J
MJ
Hamilton
Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Boston, MA 02115, USA.
Bonnie
B
Cao
Harvard Medical School, Boston, MA 02115, USA. Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Boston, MA 02115, USA.
Joshua R
JR
Korzenik
Harvard Medical School, Boston, MA 02115, USA. Miraca Life Sciences, Newton, MA 02464, USA.
Jonathan N
JN
Glickman
Institute for Stem Cell Biology and Regenerative Medicine (inStem), Bangalore 560065, India.
Praveen K
PK
Vemula
Weill Cornell Medical College, New York, NY 10065, USA.
Laurie H
LH
Glimcher
The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Harvard Medical School, Boston, MA 02115, USA. Division of Gastroenterology, Massachusetts General Hospital, Boston, MA 02114, USA. rlanger@mit.edu jmkarp@partners.org ctraverso@partners.org.
Giovanni
G
Traverso
The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Cambridge, MA 02139, USA. rlanger@mit.edu jmkarp@partners.org ctraverso@partners.org.
Robert
R
Langer
Center for Regenerative Therapeutics, Biomedical Research Institute, Brigham and Women's Hospital, Boston, MA 02115, USA. Harvard Medical School, Boston, MA 02115, USA. Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Cambridge, MA 02139, USA. Harvard Stem Cell Institute, Cambridge, MA 02138, USA. rlanger@mit.edu jmkarp@partners.org ctraverso@partners.org.
Jeffrey M
JM
Karp
D000818:Animals; D001706:Biopsy; D003092:Colitis / Q000188:drug therapy / Q000473:pathology; D003106:Colon / Q000187:drug effects / Q000473:pathology; D003907:Dexamethasone / Q000494:pharmacology / Q000627:therapeutic use; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000008:administration & dosage*; D007249:Inflammation / Q000188:drug therapy* / Q000473:pathology*; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000473:pathology*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008807:Mice, Inbred BALB C; D016896:Treatment Outcome
D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D003907:Dexamethasone