Yeruva Taj, Morris Robert J, Zhao Luke, Kofinas Peter, Duncan Gregg A
Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA.
Department of Chemical & Biomolecular Engineering, University of Maryland, College Park, MD 20742, USA.
bioRxiv. 2024 Aug 19:2024.08.16.608319. doi: 10.1101/2024.08.16.608319.
gelling polymeric biomaterials have proven useful as drug delivery vehicles to enable sustained release at sites of disease or injury. However, if delivered to mucosal tissues, such as the eyes, nose, gastrointestinal, and cervicovaginal tract, these gels must also possess the ability to adhere to an epithelium coated in mucus. Towards this end, we report a new rapid gelling polyethylene glycol-based hydrogel. Unlike other chemistries that enable rapid gel formation which form via irreversible covalent bonds, we use a bio-reducible linker allowing the gels to be naturally degraded over several days once administered. We identified a set of 6 lead formulations, which rapidly form into disulfide-linked PEG hydrogels in 30 seconds or less. These rapidly forming PEG hydrogels were also able to conform and adhere to mucosal tissues via PEG-mucin entanglements and hydrogen bonding. Controlled release of protein-based cargoes from the PEG gels was achieved over several hours whereas 40 nm nanoparticle-based cargos were retained over 24 hours. We also found these rapid in situ forming PEG gels were well-tolerated by mammalian cells. These studies support further testing and development of rapid forming PEG gels for drug delivery to improve therapeutic retention and efficacy at mucosal sites.
凝胶状聚合物生物材料已被证明可作为药物递送载体，在疾病或损伤部位实现持续释放。然而，如果将这些凝胶递送至粘膜组织，如眼睛、鼻子、胃肠道和宫颈阴道 tract，它们还必须具备粘附于覆盖有粘液的上皮的能力。为此，我们报道了一种新型的基于聚乙二醇的快速凝胶化水凝胶。与其他通过不可逆共价键形成快速凝胶的化学方法不同，我们使用了一种可生物还原的连接子，使得凝胶在给药后能够在几天内自然降解。我们确定了一组6种先导配方，它们能在30秒或更短时间内迅速形成二硫键连接的聚乙二醇水凝胶。这些快速形成的聚乙二醇水凝胶还能够通过聚乙二醇-粘蛋白缠结和氢键作用贴合并粘附于粘膜组织。基于蛋白质的载药从聚乙二醇凝胶中的控释可持续数小时，而基于40纳米纳米颗粒的载药则可保留24小时。我们还发现这些快速原位形成的聚乙二醇凝胶对哺乳动物细胞具有良好的耐受性。这些研究支持进一步测试和开发快速形成的聚乙二醇凝胶用于药物递送，以提高在粘膜部位的治疗保留率和疗效。
