Flanagan Michael, Gan Qi, Sheth Saahil, Schafer Rachel, Ruesing Samuel, Winter Linda E, Toth Karoly, Zustiak Silviya P, Montaño Adriana M
Department of Pediatrics, School of Medicine, Saint Louis University, St. Louis, MO 63104, USA.
Department of Biomedical Engineering, Saint Louis University, St. Louis, MO 63103, USA.
Pharmaceuticals (Basel). 2023 Jun 27;16(7):931. doi: 10.3390/ph16070931.
Morquio A disease is a genetic disorder resulting in N-acetylgalactosamine-6-sulfate sulfatase (GALNS) deficiency, and patients are currently treated with enzyme replacement therapy via weekly intravenous enzyme infusions. A means of sustained enzyme delivery could improve patient quality of life by reducing the administration time, frequency of hospital visits, and treatment cost. In this study, we investigated poly(ethylene-glycol) (PEG) hydrogels as a tunable, hydrolytically degradable drug delivery system for the encapsulation and sustained release of recombinant human GALNS (rhGALNS). We evaluated hydrogel formulations that optimized hydrogel gelation and degradation time while retaining rhGALNS activity and sustaining rhGALNS release. We observed the release of active rhGALNS for up to 28 days in vitro from the optimized formulation. rhGALNS activity was preserved in the hydrogel relative to buffer over the release window, and encapsulation was found to have no impact on the rhGALNS structure when measured by intrinsic fluorescence, circular dichroism, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). In vivo, we monitored the retention of fluorescently labeled rhGALNS in C57BL/6 albino mice when administered via subcutaneous injection and observed rhGALNS present for up to 20 days when delivered in a hydrogel versus 7 days in the buffer control. These results indicate that PEG hydrogels are suitable for the encapsulation, preservation, and sustained release of recombinant enzymes and may present an alternative method of delivering enzyme replacement therapies that improve patient quality of life.
莫尔基奥A病是一种遗传性疾病，由N-乙酰半乳糖胺-6-硫酸酯硫酸酯酶（GALNS）缺乏引起，目前患者通过每周静脉注射酶进行酶替代治疗。一种持续给药的方法可以通过减少给药时间、医院就诊频率和治疗成本来提高患者的生活质量。在本研究中，我们研究了聚乙二醇（PEG）水凝胶作为一种可调节、可水解降解的药物递送系统，用于重组人GALNS（rhGALNS）的包封和持续释放。我们评估了优化水凝胶凝胶化和降解时间的水凝胶配方，同时保留rhGALNS活性并维持rhGALNS释放。我们观察到优化配方在体外可释放活性rhGALNS长达28天。在释放窗口期间，相对于缓冲液，rhGALNS活性在水凝胶中得以保留，并且通过内在荧光、圆二色性和十二烷基硫酸钠-聚丙烯酰胺凝胶电泳（SDS-PAGE）测量发现包封对rhGALNS结构没有影响。在体内，当通过皮下注射给药时，我们监测了荧光标记的rhGALNS在C57BL/6白化小鼠体内的保留情况，观察到当以水凝胶形式递送时，rhGALNS可存在长达20天，而在缓冲液对照中则为7天。这些结果表明，PEG水凝胶适用于重组酶的包封、保存和持续释放，可能提供一种改善患者生活质量的酶替代疗法的替代给药方法。
