Ultrasound-mediated gastrointestinal drug delivery.
There is a significant clinical need for rapid and efficient delivery of drugs directly to the site of diseased tissues for the treatment of gastrointestinal (GI) pathologies, in particular, Crohn's and ulcerative colitis. However, complex therapeutic molecules cannot easily be delivered through the GI tract because of physiologic and structural barriers. We report the use of ultrasound as a modality for enhanced drug delivery to the GI tract, with an emphasis on rectal delivery. Ultrasound increased the absorption of model therapeutics inulin, hydrocortisone, and mesalamine two- to tenfold in ex vivo tissue, depending on location in the GI tract. In pigs, ultrasound induced transient cavitation with negligible heating, leading to an order of magnitude enhancement in the delivery of mesalamine, as well as successful systemic delivery of a macromolecule, insulin, with the expected hypoglycemic response. In a rodent model of chemically induced acute colitis, the addition of ultrasound to a daily mesalamine enema (compared to enema alone) resulted in superior clinical and histological scores of disease activity. In both animal models, ultrasound treatment was well tolerated and resulted in minimal tissue disruption, and in mice, there was no significant effect on histology, fecal score, or tissue inflammatory cytokine levels. The use of ultrasound to enhance GI drug delivery is safe in animals and could augment the efficacy of GI therapies and broaden the scope of agents that could be delivered locally and systemically through the GI tract for chronic conditions such as inflammatory bowel disease.
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Carl M
CM
Schoellhammer
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Faculty of Chemical Engineering, Technion-Israel Institute of Technology, Haifa 32000, Israel.
Avi
A
Schroeder
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Ruby
R
Maa
Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
Gregory Yves
GY
Lauwers
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Albert
A
Swiston
Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Michael
M
Zervas
The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Ross
R
Barman
The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Angela M
AM
DiCiccio
Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
William R
WR
Brugge
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Daniel G
DG
Anderson
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. dblank@mit.edu rlanger@mit.edu ctraverso@partners.org.
Daniel
D
Blankschtein
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. dblank@mit.edu rlanger@mit.edu ctraverso@partners.org.
Robert
R
Langer
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. dblank@mit.edu rlanger@mit.edu ctraverso@partners.org.
Giovanni
G
Traverso
D000818:Animals; D003092:Colitis / Q000188:drug therapy; D016503:Drug Delivery Systems; D041981:Gastrointestinal Tract; D014465:Ultrasonics