Localized delivery of glycosaminoclycan ethers for the treatment of radiation-induced proctitis

摘要 放射性直肠炎(RIP)通常被认为是一种慢性炎症性疾病，涉及 直肠。病理学研究表明，患者的症状与炎症有关。 沿着直肠衬里上皮的病变。这项拨款申请建议将小说 硫酸化阴离子多糖，半合成糖胺聚糖醚(SAGES)与丝绸- 在直肠内提供治疗相关剂量的弹性蛋白聚合物(SELP)基质 通过一种精心设计的原位凝胶灌肠。SELP在房间中以水溶液的形式存在 温度，并在体温下形成固体水凝胶基质，使它们能够防止 快速清除鼠尾草并增强其在直肠和直肠下腔的定位 肠子。我们假设局部注射鼠尾草可以保护直肠免受损伤。 通过改善RIP来提高疗效。为了检验这一假说，有三个 具体目标是：1)合成和表征具有合适流变性的SELP 鼠尾草经直肠给药的性质及释药特性；2)考察其生物分布 SELP水凝胶提供的鼠尾草对辐射诱导小鼠模型的疗效 3)阐明肥大细胞在放射性直肠炎中的关键效应细胞类型，以及 评估SELP水凝胶中的SAGE减轻肥大细胞介导的直肠炎的能力。这项建议 是翻译性质的，并在使用重组SELP的新适应症方面具有创新性 提供我们的专利鼠尾草化合物，具有强大的抗炎和止痛特性。 该项目意义重大，因为它将减少RIP对受影响患者的不良影响 人口。这项工作将为这两个系统建立早期的临床前验证 并提供有关消炎止痛属性的详细知识 鼠尾草-SELP化合物。

ABSTRACT Radiation-induced proctitis (RIP) is often considered a chronic inflammatory disease involving the rectum. Pathologic studies have shown patient symptoms are correlated with inflammatory lesions along the epithelium lining the rectum. This grant application proposes to combine novel sulfated anionic polysaccharides, semisynthetic glycosaminoglycan ethers (SAGEs) with silk- elastinlike protein polymer (SELP) matrices to deliver therapeutically relevant doses in the rectum via a precisely engineered in situ gelling enema. SELPs exist as aqueous solutions at room temperature, and form a solid hydrogel matrix at body temperature, enabling them to prevent rapid clearance of the SAGE and enhance its localization in the lumen of the rectum and lower bowel. We hypothesize that localized delivery of SAGE can protect the rectum from damage caused by radiotherapy and improve efficacy by ameliorating RIP. To test this hypothesis three specific aims are proposed: 1) To synthesize and characterize SELPs with appropriate rheological properties and release profiles for rectal delivery of SAGE; 2) To investigate the biodistribution and efficacy of SAGE delivered from SELP hydrogels in a murine model of radiation-induced proctitis; 3) To elucidate mast cells as a key effector cell type in radiation-induced proctitis and assess SAGE in SELP hydrogels’ ability to attenuate mast cell mediated proctitis. This proposal is translational in nature and innovative in the new indication for use of recombinant SELPs to deliver our patented SAGE compounds with potent anti-inflammatory and anti-pain properties. The project is significant in that it will reduce the adverse effects of RIP in the affected patient populations. This work will establish the early-stage preclinical validation for these two systems and provide detailed knowledge about the inflammation and pain attenuation properties of the SAGE-SELP compounds.