Abstract
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.
Highlights
Radiation induced proctitis (RIP) is a common side effect of pelvic radiotherapies which aim to treat lower abdominal cancers such as prostate, uterine, vaginal, and cervical cancers [1]
The occurrence of acute RIP can lead to cessation of radiotherapy schedules which are needed for cancer treatment
At 0.16-g stimulus, animals receiving GM–silk-elastinlike polymers (SELPs) (+3.3 ± 20.7%) had a significantly lower change in response rate compared to animals receiving Phosphate buffered saline (PBS) (+40.0 ± 20.0%)
Summary
Radiation induced proctitis (RIP) is a common side effect of pelvic radiotherapies which aim to treat lower abdominal cancers such as prostate, uterine, vaginal, and cervical cancers [1]. The anatomical fixed position makes the rectum especially susceptible to exposure from ionizing radiation, commonly resulting in inflammation. Of the patients receiving lower abdominal radiotherapy, it is estimated that 5–20% will develop some form of acute and/or chronic RIP [2]. Acute RIP occurs within days to months following irradiation and can result in common symptomology of abdominal pain/cramps, diarrhea, hematochezia, and other adverse effects [2,3]. The occurrence of acute RIP can lead to cessation of radiotherapy schedules which are needed for cancer treatment. Chronic RIP typically develops months to years following irradiation, and is met with more debilitating
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