An Oligomeric Sulfated Hyaluronan and Silk-Elastinlike Polymer Combination Protects against Murine Radiation Induced Proctitis.
Douglas SteinhauffMark Martin JensenEthan GriswoldJolanta D JedrzkiewiczJoseph CappelloSiam OottamasathienHamidreza GhandehariPublished in: Pharmaceutics (2022)
Semisynthetic glycosaminoglycan ethers (SAGEs) are short, sulfated hyaluronans which combine the natural properties of hyaluronan with chemical sulfation. In a murine model, SAGEs provide protection against radiation induced proctitis (RIP), a side effect of lower abdominal radiotherapy for cancer. The anti-inflammatory effects of SAGE have been studied in inflammatory diseases at mucosal barrier sites; however, few mechanisms have been uncovered necessitating high throughput methods. SAGEs were combined with silk-elastinlike polymers (SELPs) to enhance rectal accumulation in mice. After high radiation exposure to the lower abdominal area, mice were followed for 3 days or until they met humane endpoints, before evaluation of behavioral pain responses and histological assessment of rectal inflammation. RNA sequencing was conducted on tissues from the 3-day cohort to determine molecular mechanisms of SAGE-SELP. After 3 days, mice receiving the SAGE-SELP combination yielded significantly lowered pain responses and amelioration of radiation-induced rectal inflammation. Mice receiving the drug-polymer combination survived 60% longer than other irradiated mice, with a fraction exhibiting long term survival. Sequencing reveals varied regulation of toll like receptors, antioxidant activities, T-cell signaling, and pathways associated with pain. This investigation elucidates several molecular mechanisms of SAGEs and exhibits promising measures for prevention of RIP.
Keyphrases
- radiation induced
- radiation therapy
- high fat diet induced
- oxidative stress
- chronic pain
- high throughput
- anti inflammatory
- single cell
- pain management
- rectal cancer
- neuropathic pain
- type diabetes
- emergency department
- insulin resistance
- spinal cord injury
- wild type
- early stage
- adipose tissue
- tyrosine kinase
- young adults
- papillary thyroid
- spinal cord
- metabolic syndrome
- lymph node metastasis
- postoperative pain
- drug induced