ID: 362986
Password: 589009

AIChE â?? Biomaterials â?? Biomaterials for Drug and Gene Delivery

Title: Topical Drug Delivery in Ulcerative Colitis Using an Inflammation-targeted Hydrogel

Authors: Sufeng Zhang, Joerg Ermann, Marc D. Succi, Allen Zhou, Jonathan N. Glickman, Praveen K. Vemula, Laurie H. Glimcher, Giovanni Traverso, Robert Langer, Jeffrey M. Karp

Ulcerative colitis (UC), one of the two main types of inflammatory bowel disease (IBD), is a chronic intestinal disorder characterized by mucosal inflammation limited to the colon [1]. A major hurdle in the treatment of UC is the lack of an effective drug delivery system to precisely deliver drugs to the sites of inflammation for higher local drug concentration, less systemic absorption, and therefore fewer side effects. To improve drug delivery in UC, we have developed an inflammation-targeted hydrogel system, made from ascorbyl palmitate listed as â??Generally Recognized as Safeâ? (GRAS) by the Food and Drug Administration (FDA). The GRAS hydrogel was assembled as described previously with minor modifications [2]. Dexamethasone (Dex) was used as a model drug, and the release of Dex from the hydrogel in vitro was quantified in different release media. To demonstrate that the hydrogel preferentially adheres to the sites of inflammation, a fluorescent dye was encapsulated in the hydrogel for
imaging purpose. Two murine colitis models, T-betâ??/â??Rag2â??/â?? Ulcerative Colitis (TRUC) [3,4] and
Dextran Sodium Sulfate (DSS) induced colitis [5], were used for animal studies. Adhesion of the hydrogel to the inflamed colon was assessed ex vivo and in vivo. The therapeutic efficacy of Dex-loaded hydrogel administered to mice with colitis via enema was compared with Dex alone, hydrogel alone or untreated mice. Systemic Dex exposure after a single enema of Dex-loaded hydrogel or Dex alone to colitic mice was quantified using blood taken from mice at different time points, and the area under the curve (AUC) was analyzed. The self-assembled hydrogel demonstrated enzymatically triggered release of Dex and preferential adherence to the inflamed colon tissue. Dex-loaded hydrogel significantly inhibited colon inflammation in the TRUC model compared to controls. Dex quantification in the serum indicated an 8-15-fold lower Dex peak serum concentrations and 4-7-fold less systemic drug exposure (analyzed by AUC) after a single enema of Dex-loaded hydrogel in comparison with Dex alone. This topical drug delivery system using inflammation-targeted hydrogels enables local drug delivery to the sites of inflammation to lower systemic toxicity, and could potentially reduce the dosing frequency owing to the improved treatment efficacy. These studies establish a proof of concept in pre-clinical murine UC models for future studies for translation to the clinic.

References:

[1] Abraham C et al., N Engl J Med, 2009, 361(21): 2066-2078.
[2] Vemula PK, et al., J Biomed Mater Res, 2011, A 97(2): 103-110. [3] Garrett WS, et al., Cell, 2007, 131(1): 33-45.
[4] Ermann J, et al., Proc Natl Acad Sci USA, 2011, 108(17): 7137-7141. [5] Yan Y et al., PLoS One, 2009, 4, e6073.