Nanoparticle delivery vehicles targeting P. gingivalis

 描述(申请人提供)：牙龈卟啉单胞菌与成人牙周炎密切相关，牙周炎是一种广泛且代价高昂的疾病，主要表现在口腔，但也与系统性疾病有关，如动脉粥样硬化和类风湿性关节炎。牙龈假单胞菌与戈登链球菌等共生生物的黏附促进了牙龈假单胞菌在口腔的初始定植，我们先前的工作确定了一种能够有效抑制这种相互作用的多肽。这项应用的主要目标是开发Ne纳米颗粒(NP)递送载体，该载体将在很长一段时间内将高局部浓度的多肽输送到口腔中被牙龈假单胞菌定植的部位。将使用两种方法。目的1通过促进与牙龈假单胞菌的多价相互作用，产生表面修饰多肽的NPs，以提高多肽的有效性。利用已建立的体外生物膜模型和牙周炎体内动物模型，将修饰后的NPs的效力与可溶性多肽进行比较。在目标2中，我们将 初步合成包裹多肽的缓释纳米粒。NPs的负载和释放性能将被优化，以使NPs至少在24小时内释放抑制浓度的多肽。一旦获得了具有所需释放特性的NPs，它们将被CAFA蛋白表面修饰，CAFA蛋白介导放线菌与S.Gordonii的共聚集。将使用体外生物膜模型和小鼠牙周炎模型来确定NP对链球菌的黏附效率，并评估缓释NPs的功能。预计通过靶向链球菌的缓释NPs，多肽将被递送并释放到口腔生物膜中通常由牙龈假单胞菌占据的利基位置，从而增加多肽抑制剂的有效性。

 DESCRIPTION (provided by applicant): Porphyromonas gingivalis is strongly associated with adult periodontitis, a widespread and costly disease that is primarily manifest in the oral cavity but also associated with systemic diseases such as atherosclerosis and rheumatoid arthritis. The adherence of P. gingivalis to commensal organisms such as Streptococcus gordonii facilitates the initial colonization of the oral cavity by P. gingivalis and our prior work identifed a peptide that potently inhibits this interaction. The main goal of this application is to develop ne nanoparticle (NP) delivery vehicles that will deliver high localized concentrations of the peptide for prolonged periods of time to sites in the oral cavity that are colonized by P. gingivalis. Two approaches will be used. Aim 1 will generate NPs that are surface‐modified with the peptide in order increase effectiveness of the peptide by facilitating multi‐valent interactions with P. gingivalis. The potency of the modified NPs will be compared to soluble peptide using established in vitro biofilm models and an in vivo animal model of periodontitis. In Aim 2, we will initially synthesize sustained release NPs that encapsulate the peptide. The load and release properties of the NPs will be optimized such that NPs will release an inhibitory concentration of the peptide for at least 24 hrs. Once NPs with the desired release properties are obtained, they will be surface modified with the CafA protein which mediates co‐aggregation of Actinomyces with S. gordonii. The efficiency of NP adherence to streptococci will be determined and the function of sustained release NPs will be assessed using both in vitro biofilm models and a mouse model of periodontitis. It is anticipated that by targeting sustained release NPs to streptococci, the peptide will be delivered and released into a niche in the oral biofilm that is normally occupied by P. gingivalis, thus increasing the effectiveness of the peptide inhibitor.