Local Application of Pyrophosphorylated Simvastatin Prevents Experimental Periodontitis.
Local Application of Pyrophosphorylated Simvastatin Prevents Experimental Periodontitis.
复制标题
DOI：
10.1007/s11095-018-2444-z
复制
发表时间：
2018-06-25
影响因子：
3.7
通讯作者：
Wang D
中科院分区：
文献类型：
--
作者：
Wang X;Jia Z;Almoshari Y;Lele SM;Reinhardt RA;Wang D
辛伐他汀（SIM）是一种广泛用于高胆固醇血症的HMG-CoA还原酶抑制剂，据报道可以改善炎症并促进骨生成。然而，它在这些潜在的次要适应症上的临床应用一直受到其缺乏成骨性和水溶性差的阻碍。为了解决这一挑战，我们建议设计并评估一种具有更好水溶性和骨亲和力的新型辛伐他汀前药的治疗效果。前药（SIM-PPi）是由SIM三聚体与焦磷酸盐（PPi）直接偶联合成的。在体外对其水溶性、亲骨性、毒性、抗炎和成骨性进行了表征和评价。然后通过每周三次注射到结扎性实验性牙周炎大鼠模型的牙龈，在体内测试其抗炎和成骨特性。体外研究表明，SIM- ppi大大提高了SIM的水溶性，并与羟基磷灰石（HA）有较强的结合。在巨噬细胞培养中，SIM-PPi抑制lps诱导的促炎细胞因子（IL-1β, IL-6）。在成骨细胞培养中，发现SIM-PPi显著增加碱性磷酸酶（ALP）活性，加速矿物沉积，证实了SIM-PPi的成骨潜力。在实验性牙周骨质流失模型的体内测试中，组织学和显微ct数据显示，与剂量相当的SIM相比，SIM- ppi在减少炎症细胞和保存牙槽骨结构方面表现出更好的预防作用。SIM-PPi可能有潜力进一步发展，以更好地临床管理牙周炎相关的骨质流失。
Simvastatin (SIM), a HMG-CoA reductase inhibitor widely prescribed for hypercholesterolemia, has been reported to ameliorate inflammation and promote osteogenesis. Its clinical applications on these potential secondary indications, however, have been hampered by its lack of osteotropicity and poor water solubility. To address this challenge, we propose to design and evaluate the therapeutic efficacy of a novel simvastatin prodrug with better water solubility and bone affinity. The prodrug (SIM-PPi) was synthesized by directly conjugating a SIM trimer to a pyrophosphate (PPi). It was characterized and evaluated in vitro for its water solubility, osteotropicity, toxicity, anti-inflammatory and osteoinductive properties. It was then tested for anti-inflammatory and osteoinductive properties in vivo by three weekly injections into gingiva of a ligature-induced experimental periodontitis rat model. In vitro studies showed that SIM-PPi has greatly improved water-solubility of SIM and shows strong binding to hydroxyapatite (HA). In macrophage culture, SIM-PPi inhibited LPS-induced pro-inflammatory cytokines (IL-1β, IL-6). In osteoblast culture, it was found to significantly increase alkaline phosphatase (ALP) activity with accelerated mineral deposition, confirming the osteogenic potential of SIM-PPi. When tested in vivo on an experimental periodontal bone-loss model, SIM-PPi exhibited a superior prophylactic effect compared to dose equivalent SIM in reducing inflammatory cells and in preserving alveolar bone structure, as shown in the histological and micro-CT data. SIM-PPi may have the potential to be further developed for better clinical management of bone loss associated with periodontitis.
登录
查看更多内容
影响因子：
14
作者：
Lee, Yeonju;Schmid, Marian J.;Reinhardt, Richard A.
通讯作者：
Reinhardt, Richard A.
影响因子：
56.9
作者：
Mundy, G;Garrett, R;Gutierrez, G
通讯作者：
Gutierrez, G
影响因子：
--
作者：
Agarwal S;Chaubey KK;Chaubey A;Agarwal V;Madan E;Agarwal MC
通讯作者：
Agarwal MC
影响因子：
4.3
作者：
Eke PI;Dye BA;Wei L;Slade GD;Thornton-Evans GO;Borgnakke WS;Taylor GW;Page RC;Beck JD;Genco RJ
通讯作者：
Genco RJ
影响因子：
6.7
作者：
Herrera, D;Sanz, M;Roldán, S
通讯作者：
Roldán, S