title: Silk-elastinlike protein polymers enhance the efficacy of a therapeutic glycosaminoglycan for prophylactic treatment of radiation-induced proctitis.
abstract: Radiation-induced proctitis (RIP) is the most common clinical adverse effect for patients receiving radiotherapy as part of the standard course of treatment for ovarian, prostate, colon, and bladder cancers. RIP limits radiation dosage, interrupts treatment, and lowers patients' quality of life. A prophylactic treatment that protects the gastrointestinal tract from deleterious effects of radiotherapy will significantly improve patient quality of life and may allow for higher and more regular doses of radiation therapy. Semi-synthetic glycosaminoglycan (GAG), generated from the sulfation of hyaluronic acid, are anti-inflammatory but have difficulty achieving therapeutic levels in many tissues. To enhance the delivery of GAG, we created an in situ gelling rectal delivery system using silk-elastinlike protein polymers (SELPs). Using solutions of SELP 815K (which contains 6 repeats of blocks comprised of 8 silk-like units, 15 elastin-like units, and 1 lysine-substituted elastin-like unit) with GAG GM-0111, we created an injectable delivery platform that transitioned in <5min from a liquid at room temperature to a hydrogel at body temperature. The hydrogels released 50% of their payload within 30min and enhanced the accumulation of GAG in the rectum compared to traditional enema-based delivery. Using a murine model of radiation-induced proctitis, the prophylactic delivery of a single dose of GAG from a SELP matrix administered prior to irradiation significantly reduced radiation-induced pain after 3, 7, and 21days by 53±4%, 47±10%, and 12±6%, respectively. Matrix-mediated delivery of GAG by SELP represents an innovative method for more effective treatment of RIP and promises to improve quality of life of cancer patients by allowing higher radiotherapy doses with improved safety.
authors.affiliation: Department of Bioengineering, University of Utah, Salt Lake City, UT 84112, USA; Utah Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Mark Martin
authors.initials: MM
authors.lastname: Jensen
authors.affiliation: Division of Urology, Section of Pediatric Urology, University of Utah, Salt Lake City, UT 84113, USA.
authors.forename: Wanjian
authors.initials: W
authors.lastname: Jia
authors.affiliation: Department of Bioengineering, University of Utah, Salt Lake City, UT 84112, USA; Utah Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Kyle J
authors.initials: KJ
authors.lastname: Isaacson
authors.affiliation: Division of Urology, Section of Pediatric Urology, University of Utah, Salt Lake City, UT 84113, USA.
authors.forename: Austin
authors.initials: A
authors.lastname: Schults
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Cappello
authors.affiliation: Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Glenn D
authors.initials: GD
authors.lastname: Prestwich
authors.affiliation: Division of Urology, Section of Pediatric Urology, University of Utah, Salt Lake City, UT 84113, USA; Department of Surgery and Division of Pediatric Urology, Primary Children's Hospital, Salt Lake City, UT 84113, USA. Electronic address: siam.oottamasathien@hsc.utah.edu.
authors.forename: Siam
authors.initials: S
authors.lastname: Oottamasathien
authors.affiliation: Department of Bioengineering, University of Utah, Salt Lake City, UT 84112, USA; Utah Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT 84112, USA; Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA. Electronic address: hamid.ghandehari@utah.edu.
authors.forename: Hamidreza
authors.initials: H
authors.lastname: Ghandehari
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D065546:Drug Liberation; D004733:Enema; D005260:Female; D006025:Glycosaminoglycans / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D020100:Hydrogels / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D051379:Mice; D010146:Pain / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D011349:Proctitis / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D011506:Proteins / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D011833:Radiation Injuries, Experimental / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D012007:Rectum / Q000378:metabolism; D012212:Rheology; D014965:X-Rays / Q000009:adverse effects
chemical_list: D006025:Glycosaminoglycans; D020100:Hydrogels; D011506:Proteins; C573821:SELP 815K
keywords: Colitis; Hyaluronic acid; Radiation Enteropathy; Radiation-induced proctitis; Semi-synthetic glycosaminoglycan (GAG); Silk-elastinlike protein polymer (SELP)