Heidebrecht Richard W, Jozefiak Thomas H, Shain Harrison C, Skrabut Eugene M, Saunders Debra, Smith Nataliya, Towner Rheal A, Hurst Robert
Glycologix, Inc., 100 Cummings Center, Beverly, Massachusetts, United States of America.
Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America.
PLoS One. 2025 Jan 24;20(1):e0317790. doi: 10.1371/journal.pone.0317790. eCollection 2025.
Chemical modification of naturally derived glycosaminoglycans (GAGs) expands their potential utility for applications in soft tissue repair and regenerative medicine. Here we report the preparation of a novel crosslinked chondroitin sulfate (200 to 2000 kilodaltons) that is both soluble in aqueous solution and microfilterable. We refer to these materials as "SuperGAGs." One can further conjugate these materials with diverse capture agents to further modify polymer properties and add new capabilities. A representative material (GLX-100) demonstrated durable restoration of bladder impermeability in a gold standard animal model of Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS). Histologic examination of the animal bladders treated with a GLX-100 SuperGAG conjugated to biotin as a reporter demonstrated that the residence time of GLX-100 is superior to chondroitin sulfate (a product that is currently used for clinical treatment of patients with IC/BPS). As expected, this novel crosslinked GAG biopolymer was restricted to the luminal surface of the bladder wall. In this communication we describe a simple and versatile synthesis of a crosslinked glycosaminoglycan (GAG) biopolymer for soft tissue repair. Chondroitin sulfate (12 kD) was crosslinked to form a water soluble and microfilterable polymer with approximately 200 to 2000 kD molecular weight. The synthesis presented here allows for control of molecular weight while avoiding formation of an extended block gel. Moreover, the procedure enables further chemical modification of the SuperGAG through the selection of a capture agent. A set of agents have been used, demonstrating the preparation of a family of SuperGAGs with diverse capabilities. We can optimize polymer properties, adjust adherence to various tissues, add reporters, and engage the biochemistry of surrounding tissues with peptides and other bioactives.
对天然来源的糖胺聚糖（GAGs）进行化学修饰，可拓展其在软组织修复和再生医学中的潜在应用价值。在此，我们报告了一种新型交联硫酸软骨素（分子量约200至2000千道尔顿）的制备方法，该硫酸软骨素可溶于水溶液且可通过微滤。我们将这些材料称为“超级糖胺聚糖（SuperGAGs）”。人们可以进一步将这些材料与多种捕获剂结合，以进一步改变聚合物的性质并增添新功能。一种代表性材料（GLX - 100）在间质性膀胱炎/膀胱疼痛综合征（IC/BPS）的金标准动物模型中，展现出对膀胱不透性的持久恢复作用。用与生物素结合作为报告分子的GLX - 100超级糖胺聚糖处理动物膀胱后的组织学检查表明，GLX - 100的驻留时间优于硫酸软骨素（一种目前用于临床治疗IC/BPS患者的产品）。正如预期的那样，这种新型交联GAG生物聚合物局限于膀胱壁的腔面。在本通讯中，我们描述了一种用于软组织修复的交联糖胺聚糖（GAG）生物聚合物的简单通用合成方法。硫酸软骨素（约12 kD）被交联形成一种分子量约为200至2000 kD的水溶性且可微滤的聚合物。此处介绍的合成方法能够控制分子量，同时避免形成延伸的块状凝胶。此外，该方法通过选择捕获剂，能够对超级糖胺聚糖进行进一步的化学修饰。已经使用了一系列试剂，展示了具有多种功能的超级糖胺聚糖家族的制备。我们可以优化聚合物性质，调整对各种组织的粘附性，添加报告分子，并通过肽和其他生物活性物质参与周围组织的生物化学过程。
