Encinas-Basurto David, Konhilas John P, Polt Robin, Hay Meredith, Mansour Heidi M
Skaggs Pharmaceutical Sciences Center, College of Pharmacy, The University of Arizona, Tucson, AZ 85721, USA.
Department of Physiology and Sarver Heart Center, The University of Arizona, Tucson, AZ 85721, USA.
Pharmaceutics. 2022 Mar 8;14(3):587. doi: 10.3390/pharmaceutics14030587.
Heart failure (HF) causes decreased brain perfusion in older adults, and increased brain and systemic inflammation increases the risk of cognitive impairment and Alzheimer’s disease (AD). Glycosylated Ang-(1-7) MasR agonists (PNA5) has shown improved bioavailability, stability, and brain penetration compared to Ang-(1-7) native peptide. Despite promising results and numerous potential applications, clinical applications of PNA5 glycopeptide are limited by its short half-life, and frequent injections are required to ensure adequate treatment for cognitive impairment. Therefore, sustained-release injectable formulations of PNA5 glycopeptide are needed to improve its bioavailability, protect the peptide from degradation, and provide sustained drug release over a prolonged time to reduce injection administration frequency. Two types of poly(D,L-lactic-co-glycolic acid) (PLGA) were used in the synthesis to produce nanoparticles (≈0.769−0.35 µm) and microparticles (≈3.7−2.4 µm) loaded with PNA5 (ester and acid-end capped). Comprehensive physicochemical characterization including scanning electron microscopy, thermal analysis, molecular fingerprinting spectroscopy, particle sizing, drug loading, encapsulation efficiency, and in vitro drug release were conducted. The data shows that despite the differences in the size of the particles, sustained release of PNA5 was successfully achieved using PLGA R503H polymer with high drug loading (% DL) and high encapsulation efficiency (% EE) of >8% and >40%, respectively. While using the ester-end PLGA, NPs showed poor sustained release as after 72 h, nearly 100% of the peptide was released. Also, lower % EE and % DL values were observed (10.8 and 3.4, respectively). This is the first systematic and comprehensive study to report on the successful design, particle synthesis, physicochemical characterization, and in vitro glycopeptide drug release of PNA5 in PLGA nanoparticles and microparticles.
心力衰竭（HF）会导致老年人脑灌注减少，而脑和全身炎症的增加会增加认知障碍和阿尔茨海默病（AD）的风险。与天然的血管紧张素（1-7）肽相比，糖基化血管紧张素（1-7）MasR激动剂（PNA5）具有更高的生物利用度、稳定性和脑渗透性。尽管取得了令人鼓舞的结果并具有众多潜在应用，但PNA5糖肽的临床应用因其半衰期短而受到限制，需要频繁注射以确保对认知障碍进行充分治疗。因此，需要PNA5糖肽的缓释注射制剂来提高其生物利用度，保护该肽不被降解，并在较长时间内提供持续的药物释放，以减少注射给药频率。合成过程中使用了两种聚（D，L-乳酸-共-乙醇酸）（PLGA）来制备负载PNA5（酯封端和酸封端）的纳米颗粒（约0.769−0.35 µm）和微粒（约3.7−2.4 µm）。进行了包括扫描电子显微镜、热分析、分子指纹光谱、粒度分析、载药量、包封率和体外药物释放在内的全面物理化学表征。数据表明，尽管颗粒大小不同，但使用载药量（% DL）和包封率（% EE）分别大于8%和大于40%的PLGA R503H聚合物成功实现了PNA5的持续释放。使用酯封端的PLGA时，纳米颗粒的持续释放效果较差，因为72小时后，几乎100%的肽都释放了出来。此外，还观察到较低的% EE和% DL值（分别为10.8和3.4）。这是第一项系统全面的研究，报告了PNA5在PLGA纳米颗粒和微粒中的成功设计、颗粒合成、物理化学表征以及体外糖肽药物释放情况。
Zotero 插件
