| Description |
Radiation-induced proctitis is an injury of the rectum that is a common adverse event occurring from radiotherapy to the lower abdominal region. This inflammatory event results in acute and chronic presentation reducing patient quality of life. Currently treatment strategies are limited with very few prophylactic approaches in the clinic. To address this unmet need I have investigated rectal controlled delivery of an antiinflammatory agent. Semisynthetic glycosaminoglycan ethers (SAGEs) are a family of glycosaminoglycan ethers consisting of short, sulfated hyaluronans. The short length and chemical sulfation of these SAGEs gives them novel therapeutic properties. These include anti-inflammatory properties such as inhibition of pattern recognition receptors, inflammatory transcription factors, and of growth of gram-negative bacteria. The global hypothesis of this dissertation is that silk-elastinlike protein polymers (SELP) improve the bioaccumulation of SAGE in the rectum and increase its radioprotective behavior. I investigated several SELP analogs for development of a liquid to semisolid drug delivery depot of SAGE. In vitro screenings focused on mechanical properties, gel formation, and release kinetics. In a prophylactic radiation-induced proctitis (RIP) mouse model, the selected SELP-SAGE combination was capable of protecting against radiation after 3 and 7 days. This combination increased the survival of mice, as determined by weight. The molecular iv mechanisms of this combination were evaluated using transcriptomics with further indications of pattern recognition receptors playing a role in the pathology of RIP. |
