Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, 986125 Nebraska Medical Center, PDD 3020, Omaha, Nebraska 68198-6125, United States.
Department of Pathology & Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States.
Mol Pharm. 2021 May 3;18(5):1992-2003. doi: 10.1021/acs.molpharmaceut.0c01196. Epub 2021 Mar 23.
Except for routine scaling and root planing, there are few effective nonsurgical therapeutic interventions for periodontitis and associated alveolar bone loss. Simvastatin (SIM), one of the 3-hydroxy-3-methylglutaryl-cosenzyme A reductase inhibitors, which is known for its capacity as a lipid-lowering medication, has been proven to be an effective anti-inflammatory and bone anabolic agent that has shown promising benefits in mitigating periodontal bone loss. The local delivery of SIM into the periodontal pocket, however, has been challenging due to SIM's poor water solubility and its lack of osteotropicity. To overcome these issues, we report a novel SIM formulation of a thermoresponsive, osteotropic, injectable hydrogel (PF127) based on pyrophosphorolated pluronic F127 (F127-PPi). After mixing F127-PPi with F127 at a 1:1 ratio, the resulting PF127 was used to dissolve free SIM to generate the SIM-loaded formulation. The thermoresponsive hydrogel's rheologic behavior, erosion and SIM release kinetics, osteotropic property, and biocompatibility were evaluated . The therapeutic efficacy of SIM-loaded PF127 hydrogel on periodontal bone preservation and inflammation resolution was validated in a ligature-induced periodontitis rat model. Given that SIM is already an approved medication for hyperlipidemia, the data presented here support the translational potential of the SIM-loaded PF127 hydrogel for better clinical management of periodontitis and associated pathologies.
除了常规的刮治和根面平整外，牙周炎和相关牙槽骨丧失几乎没有有效的非手术治疗干预措施。辛伐他汀（SIM）是 3-羟基-3-甲基戊二酰基辅酶 A 还原酶抑制剂之一，以其降脂药物的能力而闻名，已被证明是一种有效的抗炎和骨合成剂，在减轻牙周骨丢失方面显示出了有希望的益处。然而，由于 SIM 水溶性差且缺乏成骨活性，将 SIM 局部递送至牙周袋一直具有挑战性。为了克服这些问题，我们报告了一种新型 SIM 制剂，即基于焦磷酸化泊洛沙姆 F127（F127-PPi）的热响应性、成骨性、可注射水凝胶（PF127）。将 F127-PPi 与 F127 以 1:1 的比例混合后，所得的 PF127 用于溶解游离 SIM 以生成载 SIM 制剂。评估了热响应水凝胶的流变行为、侵蚀和 SIM 释放动力学、成骨活性和生物相容性。在结扎诱导的牙周炎大鼠模型中验证了载 SIM 的 PF127 水凝胶对牙周骨保存和炎症消退的治疗效果。鉴于 SIM 已经是一种用于治疗高血脂的批准药物，这里提供的数据支持载 SIM 的 PF127 水凝胶在更好地临床管理牙周炎和相关病理方面的转化潜力。
