文献：Farnesal-loaded pH-sensitive polymeric micelles provided efective prevention and treatment on dental caries

文献链接：https://jnanobiotechnology.biomedcentral.com/articles/10.1186/s12951-020-00633-2

作者：Youping Yi, Lujun Wang, Lin Chen, Yan Lin, Zhongling Luo, Zhenyu Chen, Ting Li, Jianming Wu,Zhirong Zhong

相关产品：HO-PEG2000-NHNH2  羟基-聚乙二醇-肼

原文摘要：Background: Farnesol is a sesquiterpene from propolis and citrus fruit that shows promising anti-bacterial activity for caries treatment and prevention, but its hydrophobicity limits the clinical application. We aimed to develop the novel polymeric micelles (PMs) containing a kind of derivative of farnesol and a ligand of pyrophosphate (PPi) that mediated PMs to adhere tightly with the tooth enamel.

Results: Farnesal (Far) was derived from farnesol and successfully linked to PEG via an acid-labile hydrazone bond to form PEG-hyd-Far, which was then conjugated to PPi and loaded into PMs to form the aimed novel drug delivery system, PPi-Far-PMs. The in vitro test about the binding of PPi-Far-PMs to hydroxyapatite showed that PPi-Far-PMs could bind rapidly to hydroxyapatite and quickly release Far under the acidic conditions. Results from the mechanical testing and the micro-computed tomography indicated that PPi-Far-PMs could restore the microarchitecture of teeth with caries. Moreover, PPi-Far-PMs diminished the incidence and severity of smooth and sulcal surface caries in rats that were infected with Streptococcus mutans while being fed with a high-sucrose diet. The anti-caries efcacy of free Far can be improved signifcantly by PPi-Far-PMs through the efective binding of it with tooth enamel via PPi.

Conclusions: This novel drug-delivery system may be useful for the treatment and prevention of dental caries as well as the targeting therapy of anti-bacterial drugs in the oral disease.

HO-PEG2000-NHNH2，即羟基-聚乙二醇-肼（或称为羟基PEG氨基肼），是一种具有特定化学结构的聚乙二醇（PEG）衍生物。HO-PEG2000-NHNH2可以作为生物偶联试剂，通过其羟基和肼基与蛋白质、多肽、抗体等生物分子上的活性基团反应，实现这些分子的共价连接。这种连接方法常用于制备生物传感器或生物标记物等。pH敏感的双扑聚合物共轭物PPi-PEG-hyd-Far是一种针对特定应用而设计的智能材料。该共轭物能在特定的pH条件下发生结构变化或释放药物，这通常是通过引入可离子化的弱酸或弱碱基团、聚电解质化合物或能在酸性条件下水解的连接段来实现的。在 PPiPEG-hyd-Far 合成中，HO-PEG2000-NHNH2 主要有以下应用：

图为：pH敏感的双扑聚合物共轭物的合成

HO-PEG2000-NHNH2在pH敏感的双扑聚合物共轭物PPi-PEG-hyd-Far合成中的应用：

合成了Te对ph敏感的双熵聚合物共轭物PPi-PEG-hyd-Far。HO-PEG2000-NHNH2用t-丁羟基碳基（Boc）保护，然后经酯化和溴化得到PPiPEG-NHNH-Boc。去除Te Boc基团，随后的酰肼反应生成PPi-PEG-hyd-Far，用1h和13C NMR对其进行鉴定。HOPEG-NHNH-Boc的特殊反应条件如下。

HO-PEG2000-NHNH2在HOPEG-NHNH-Boc合成中的应用：

将三乙胺加入到HO-PEG2000-NHNH2的甲醇搅拌溶液中。将Te混合物冷却，在反应溶液中缓慢加入二叔丁酯。将Te反应混合物搅拌，然后加热至室温，搅拌。Te溶液在真空下浓缩，产物在无水醚中沉淀三次，真空干燥过夜，低温保存。

图为：PPi-Far-PMs与羟基磷灰石颗粒的结合能力

结论：HO-PEG2000-NHNH2 中的肼基（-NHNH2）可以与合成过程中的其他分子发生反应，起到连接不同部分的作用。例如，在合成 PPiPEG-hyd-Far 的过程中，它的肼基可以与含有醛基等反应性基团的分子进行反应，形成腙键（-NHN=C-）。而法尼醛（Far）中含有醛基，HO-PEG2000-NHNH2 的肼基可与法尼醛的醛基反应，将法尼醛连接到整个分子结构中，起到连接亲水端和疏水端的桥梁作用，最终形成 PPiPEG-hyd-Far。在 PPiPEG-hyd-Far 这种靶向给药系统中，HO-PEG2000-NHNH2 参与构建的结构能够实现药物的靶向递送。 HO-PEG2000-NHNH2 连接的部分在整个过程中起到稳定结构、促进药物与靶向配体结合的作用，从而提高药物的靶向性和效果。