Silk-elastinlike copolymers enhance bioaccumulation of semisynthetic glycosaminoglycan ethers for prevention of radiation induced proctitis.
Silk-elastinlike copolymers enhance bioaccumulation of semisynthetic glycosaminoglycan ethers for prevention of radiation induced proctitis.
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DOI：
10.1016/j.jconrel.2021.03.001
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发表时间：
2021-04-10
影响因子：
10.8
通讯作者：
Ghandehari, H.
中科院分区：
文献类型：
--
作者：
Steinhauff, D.;Jensen, M.;Talbot, M.;Jia, W.;Isaacson, K.;Jedrzkiewicz, J.;Cappello, J.;Oottamasathien, S.;Ghandehari, H.
关键词：
放射性诱发的直肠炎（RIP）是一种使人衰弱的不良事件，通常发生在下腹部放射治疗期间。缺乏预防性治疗策略导致患者生活质量下降，放疗计划中断，以及由于剂量限制性毒性而限制放疗效果。半合成糖胺聚糖醚（SAGE）显示出对RIP的保护作用。然而，在直肠组织中停留时间短限制了它们的效用。我们研究了SAGE类似物GM-0111的控制递送，GM-0111具有抗RIP的功效，使用一系列温度响应聚合物来比较不同的相变行为、机械性能和释放动力学如何影响直肠生物积累。聚（乳酸）-共（乙醇酸）-嵌段聚（乙二醇）-嵌段聚（乳酸）-共（乙醇酸）共聚物进行宏观相分离，在凝胶化过程中排出50%的药物。Poloxamer组合物在1小时内释放出gm0111货物，而丝绸弹性蛋白样共聚物（selp）在12小时内可以控制释放。利用荧光成像和共聚焦显微镜评估生物积累。SELP- 415k是一种SELP类似物，具有4个丝单位、15个弹性蛋白单位和一个弹性蛋白单位，在单体重复序列中有赖氨酸残基，其直肠生物积累最高。然后使用SELP-415K GM-0111组合物在小鼠RIP模型中对辐射诱导的组织损伤提供局部保护。使用SELP-415K直肠给药SAGE显著减少了行为疼痛反应，与辐照对照组或传统给药方法相比，减少了动物质量损失。组织学评分显示，由SELP-415K递送GM-0111治疗的动物RIP损伤得到改善。热响应性selp通过液体到半固体的转变增强了生物积累，改善了GM-0111对小鼠的直肠递送和RIP模型的辐射防护。
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 hour, while silk-elastinlike copolymers (SELPs) enabled controlled release over a period of 12 hours. 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.
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影响因子：
5.8
作者：
Barichello, JM;Morishita, M;Nagai, T
通讯作者：
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DOI：
10.1016/s0360-3016(00)00744-6
发表时间：
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作者：
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