Mol Pharm. 2023 Nov 6;20(11):5631-5645. doi: 10.1021/acs.molpharmaceut.3c00508. Epub 2023 Sep 29.
Periodontitis (PD) is a severe inflammatory gum pathology that damages the periodontal soft tissue and bone. It is highly prevalent in the US, affecting more than 47% of adults. Besides routine scaling and root planing, there are few effective treatments for PD. Developed as an effective treatment for hyperlipidemia, simvastatin (SIM) is also known for its well-established anti-inflammatory and osteogenic properties, suggesting its potential utility in treating PD. Its clinical translation, however, has been impeded by its poor water-solubility, lack of osteotropicity, and side effects (e.g., hepatoxicity) associated with systemic exposure. To address these challenges, an -(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based thermoresponsive polymeric prodrug of SIM (ProGel-SIM) was developed as a local therapy for PD. Its aqueous solution is free-flowing at 4 °C and transitions into a hydrogel at ∼30 °C, allowing for easy local application and retention. After a thorough characterization of its physicochemical properties, ProGel-SIM was administered weekly into the periodontal pocket of an experimental rat model of PD. At 3 weeks post initiation of the treatment, the animals were euthanized with palate isolated for μ-CT and histological analyses. When compared to dose equivalent simvastatin acid (SMA, active form of SIM) treatment, the rats in the ProGel-SIM treated group showed significantly higher periodontal bone volume (0.34 mm vs 0.20 mm, = 0.0161) and less neutrophil (PMN) infiltration ( < 0.0001) and IL-1β secretion ( = 0.0036). No measurable side effect was observed. Collectively, these results suggest that ProGel-SIM may be developed as a promising drug candidate for the effective clinical treatment of PD.
牙周炎（PD）是一种严重的炎症性牙龈疾病，会破坏牙周软组织和骨骼。它在美国非常普遍，影响超过 47%的成年人。除了常规的洁治和根面平整外，PD 几乎没有有效的治疗方法。辛伐他汀（SIM）作为一种有效的降脂药物，具有良好的抗炎和成骨特性，因此被认为在治疗 PD 方面具有潜在的应用价值。然而，由于其水溶性差、缺乏成骨性和与全身暴露相关的副作用（如肝毒性），其临床应用受到了阻碍。为了解决这些挑战，开发了一种基于 -(2-羟丙基)甲基丙烯酰胺（HPMA）共聚物的 SIM 热响应性聚合物前药（ProGel-SIM），作为 PD 的局部治疗药物。其水溶液在 4°C 时自由流动，在约 30°C 时转变为水凝胶，便于局部应用和保留。在对其理化性质进行了全面表征后，将 ProGel-SIM 每周一次注入 PD 实验大鼠模型的牙周袋中。在治疗开始后 3 周，用安乐死法处死动物，分离腭骨进行 μ-CT 和组织学分析。与等剂量的辛伐他汀酸（SMA，SIM 的活性形式）治疗相比，ProGel-SIM 治疗组的大鼠牙周骨量明显更高（0.34mm 比 0.20mm， = 0.0161），中性粒细胞（PMN）浸润明显减少（ < 0.0001），IL-1β分泌明显减少（ = 0.0036）。未观察到可测量的副作用。综上所述，这些结果表明，ProGel-SIM 可能被开发为治疗 PD 的有效临床治疗的有前途的候选药物。
