Silk-elastinlike protein polymers enhance the efficacy of a therapeutic glycosaminoglycan for prophylactic treatment of radiation-induced proctitis

JOURNAL OF CONTROLLED RELEASE

卷:263

Article; Proceedings Paper

Jensen, Mark Martin^1,2  Jia, Wanjian³  Isaacson, Kyle J.^1,2  Schults, Austin³  Cappello, Joseph⁴  Prestwic, Glenn D.⁵  Oottamasathien, Siam^3,6,7  Ghandehari, Hamidreza^1,2,4 

[1] Univ Utah, Dept Bioengn, Salt Lake City, UT 84112 USA

[2] Univ Utah, Utah Ctr Nanomed, Nano Inst Utah, Salt Lake City, UT 84112 USA

[3] Univ Utah, Div Urol, Sect Pediat Urol, Salt Lake City, UT 84113 USA

[4] Univ Utah, Dept Pharmaceut & Pharmaceut Chem, Salt Lake City, UT 84112 USA

[5] Univ Utah, Dept Med Chem, Salt Lake City, UT 84112 USA

[6] Primary Childrens Med Ctr, Dept Surg, Salt Lake City, UT 84113 USA

[7] Primary Childrens Med Ctr, Div Pediat Urol, Salt Lake City, UT 84113 USA

关键词: Semi-synthetic glycosaminoglycan (GAG);    Radiation-induced proctitis;    Silk-elastinlike protein polymer (SELP);    Radiation Enteropathy;    Hyaluronic acid;    Colitis;   

DOI  :  10.1016/j.jconrel.2017.02.025

来源: Elsevier

【 摘 要 】

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 <5 min from a liquid at room temperature to a hydrogel at body temperature. The hydrogels released 50% of their payload within 30 min 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 21 days 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. (C) 2017 Elsevier B.V. All rights reserved.

【 授权许可】

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