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， 直肠病理学研究表明，患者的症状与炎症相关。 沿着直肠衬里上皮的沿着病变。这项拨款申请建议将联合收割机 硫酸化阴离子多糖，半合成糖胺聚糖醚（SAGE）与丝- 在直肠中递送治疗相关剂量的弹性蛋白样蛋白聚合物（SELP）基质 通过一种精确设计的原位凝胶灌肠剂。SELP在室温下以水溶液形式存在 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SAGE，并增强其在直肠腔内的定位， 肠子我们推测SAGE局部给药可以保护直肠免受损伤 并通过改善RIP来提高疗效。为了验证这一假设， 提出了具体的目标：1）合成和表征具有适当流变性的SELP SAGE直肠给药的性质和释放曲线; 2）研究生物分布 SELP水凝胶递送的SAGE在辐射诱导的小鼠模型中的作用和功效 3）阐明肥大细胞作为辐射诱导的直肠炎中的关键效应细胞类型， 评估SELP水凝胶中SAGE减弱肥大细胞介导的直肠炎的能力。这项建议 在性质上是翻译的，在重组SELP的新适应症中具有创新性， 提供具有强效抗炎和抗疼痛特性的SAGE专利化合物。 该项目的重要性在于它将减少RIP对受影响患者的不良影响 人口。这项工作将建立这两个系统的早期临床前验证 并提供有关炎症和疼痛衰减特性的详细知识， SAGE-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.