Authors:
D. Scott Wilson and Niren Murthy
Summary:
Oxidative stress, a cytopathic consequence of excessive production of reactive oxygen species (ROS) is implicated in the development and persistence of many inflammatory diseases, including inflammatory bowel disease, acute lung injury, myocardial infarct, and reperfusion injury. For this reason, ROS provide a molecular beacon for targeting therapeutics to treat these and other inflammatory diseases. In this presentation, we introduce a new ROS-sensitive polymer for drug delivery composed of ROS sensitive thioketal linkages. Homo and copolymer poly(thioketals) (PTKs) were synthesized using the acetal exchange reaction between a variety of dimercaptans and 2,2-dimethoxypropane. PTKs have been shown to degrade in hours in the presence of supper oxide, but are stable to pHs from 1.0- 14.0 over the same time period. ROS sensitive microparticles loaded with both hydrophobic small molecules and hydrophilic biomolecules such as proteins and siRNA have been formulated from PTKs. Cell culture experiments demonstrate that dye-containing microparticles formulated from PTKs degrade more rapidly in cells that overproduce superoxide. This conclusion is based off of results that show increased dye release into cells treated with dye-containing microparticles and subsequently with the endotoxin lipopolysaccharide (LPS), which is known to cause macrophages to overproduce supper oxide, when compared to cells receiving only dye-containing microparticles and no LPS. These results demonstrate the ability of TK microparticles to target therapeutics to cells or regions of the body where there is an excess of ROS such as in and around inflamed tissue. We are currently using siRNA-loaded TK microparticles to treat inflammatory bowel disease.
Source:
The 236th American Chemical Society National Meeting; Philadelphia, PA, Franklin 1, Oral, 8:30 AM-11:25 AM (08/19/08)