Nanoparticle delivery vehicles targeting P. gingivalis

 描述（由申请人提供）：牙龈卟啉单胞菌与成人牙周炎密切相关，成人牙周炎是一种广泛且昂贵的疾病，主要表现在口腔中，但也与全身性疾病如动脉粥样硬化和类风湿性关节炎相关。牙龈卟啉单胞菌对口腔生物体如戈登链球菌的粘附促进牙龈卟啉单胞菌在口腔中的初始定殖，并且我们先前的工作鉴定了有效抑制这种相互作用的肽。本申请的主要目标是开发新的纳米颗粒（NP）递送载体，其将高局部浓度的肽长时间递送至口腔中被牙龈卟啉单胞菌定殖的部位。将采用两种方法。目的1将产生用肽表面修饰的NP，以便通过促进与牙龈卟啉单胞菌的多价相互作用来增加肽的有效性。使用建立的体外生物膜模型和牙周炎的体内动物模型，将修饰的NP的效力与可溶性肽进行比较。在目标2中，我们 最初合成包封肽的持续释放NP。将优化NP的负载和释放性质，使得NP将释放抑制浓度的肽至少24小时。一旦获得具有所需释放特性的NP，它们将用介导放线菌与S. gordonii。将使用体外生物膜模型和牙周炎小鼠模型来确定NP粘附链球菌的效率，并评估缓释NP的功能。预期通过将缓释NP靶向链球菌，肽将被递送并释放到口腔生物膜中通常被牙龈卟啉单胞菌占据的小生境中，从而增加肽抑制剂的有效性。

 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.