Department of Biomedical Engineering, University of Utah, Salt Lake City, UT 84112, USA; Utah Center for Nanomedicine, University of Utah, Salt Lake City, UT 84112, USA.
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA.
J Control Release. 2021 Apr 10;332:503-515. doi: 10.1016/j.jconrel.2021.03.001. Epub 2021 Mar 7.
Radiation-induced proctitis (RIP) is a debilitating adverse event that occurs commonly during lower abdominal radiotherapy. The lack of prophylactic treatment strategies leads to diminished patient quality of life, disruption of radiotherapy schedules, and limitation of radiotherapy efficacy due to dose-limiting toxicities. Semisynthetic glycosaminoglycan ethers (SAGE) demonstrate protective effects from RIP. However, low residence time in the rectal tissue limits their utility. We investigated controlled delivery of GM-0111, a SAGE analogue with demonstrated efficacy against RIP, using a series of temperature-responsive polymers to compare how distinct phase change behaviors, mechanical properties and release kinetics influence rectal bioaccumulation. Poly(lactic acid)-co-(glycolic acid)-block-poly(ethylene glycol)-block-poly(lactic acid)-co-(glycolic acid) copolymers underwent macroscopic phase separation, expelling >50% of drug during gelation. Poloxamer compositions released GM-0111 cargo within 1 h, while silk-elastinlike copolymers (SELPs) enabled controlled release over a period of 12 h. Bioaccumulation was evaluated using fluorescence imaging and confocal microscopy. SELP-415K, a SELP analogue with 4 silk units, 15 elastin units, and one elastin unit with lysine residues in the monomer repeats, resulted in the highest rectal bioaccumulation. SELP-415K GM-0111 compositions were then used to provide localized protection from radiation induced tissue damage in a murine model of RIP. Rectal delivery of SAGE using SELP-415K significantly reduced behavioral pain responses, and reduced animal mass loss compared to irradiated controls or treatment with traditional delivery approaches. Histological scoring showed RIP injury was ameliorated for animals treated with GM-0111 delivered by SELP-415K. The enhanced bioaccumulation provided by thermoresponsive SELPs via a liquid to semisolid transition improved rectal delivery of GM-0111 to mice and radioprotection in a RIP model.
放射性直肠炎（RIP）是一种常见于下腹部放射治疗的衰弱性不良反应。由于缺乏预防性治疗策略，导致患者生活质量下降、放射治疗计划中断以及放射治疗效果受限，出现剂量限制毒性。半合成糖胺聚糖醚（SAGE）对 RIP 具有保护作用。然而，在直肠组织中的停留时间较短限制了其应用。我们使用一系列温度响应性聚合物来研究 GM-0111（一种已证明对 RIP 有效的 SAGE 类似物）的控制释放，以比较不同的相转变行为、机械性能和释放动力学如何影响直肠生物累积。聚（乳酸-共-乙醇酸）-嵌段-聚乙二醇-嵌段-聚（乳酸-共-乙醇酸）共聚物发生宏观相分离，在凝胶化过程中排出超过 50%的药物。泊洛沙姆组合物在 1 小时内释放 GM-0111 货物，而丝弹性蛋白样共聚物（SELPs）则可以在 12 小时内进行控制释放。通过荧光成像和共焦显微镜评估生物累积。具有 4 个丝单元、15 个弹性蛋白单元和一个单体重复中赖氨酸残基的弹性蛋白单元的 SELP-415K，导致直肠生物累积最高。然后使用 SELP-415K 提供 GM-0111 的局部保护，以防止 RIP 小鼠模型中的辐射诱导的组织损伤。直肠给予 SELP-415K 中的 SAGE 可显著减轻行为性疼痛反应，并减少与照射对照或传统递送方法治疗的动物体重减轻。组织学评分表明，用 SELP-415K 递送 GM-0111 治疗的动物的 RIP 损伤得到改善。通过从液体到半固体的转变提供的热响应性 SELP 的增强生物累积改善了 GM-0111 在小鼠中的直肠递送和 RIP 模型中的放射防护作用。
