Serri Carla, Quagliariello Vincenzo, Cruz-Maya Iriczalli, Guarino Vincenzo, Maurea Nicola, Giunchedi Paolo, Rassu Giovanna, Gavini Elisabetta
Department of Medicine, Surgery and Pharmacy, University of Sassari, Via Muroni 23/A, 07100 Sassari, Italy.
Division of Cardiology, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Naples, Italy.
Pharmaceutics. 2024 Jul 25;16(8):985. doi: 10.3390/pharmaceutics16080985.
Anthracycline-based therapies exert endothelial damages through peroxidation and the production of proinflammatory cytokines, resulting in a high risk of cardiovascular complications in cancer patients. Hyaluronic acid-based hybrid nanoparticles (LicpHA) are effective pharmacological tools that can target endothelial cells and deliver drugs or nutraceuticals. This study aimed to prepared and characterized a novel LicpHA loaded with Rutin (LicpHA Rutin), a flavonoid with high antioxidant and anti-inflammatory properties, to protect endothelial cells against epirubicin-mediated endothelial damages. LicpHA Rutin was prepared using phosphatidylcholine, cholesterol, poloxamers, and hyaluronic acid by a modified nanoprecipitation technique. The chemical-physical characterization of the nanoparticles was carried out (size, zeta potential, morphology, stability, thermal analysis, and encapsulation efficiency). Cytotoxicity studies were performed in human endothelial cells exposed to epirubicin alone or in combination with Free-Rutin or LicpHA Rutin. Anti-inflammatory studies were performed through the intracellular quantification of NLRP-3, MyD-88, IL-1β, IL-6, IL17-α, TNF-α, IL-10, and IL-4 using selective ELISA methods. Morphological studies via TEM and image analysis highlighted a heterogeneous population of LicpHA particles with non-spherical shapes (circularity equal to 0.78 ± 0.14), and the particle size was slightly affected by Rutin entrapment (the mean diameter varied from 179 ± 4 nm to 209 ± 4 nm). Thermal analysis and zeta potential analyses confirmed the influence of Rutin on the chemical-physical properties of LicpHA Rutin, mainly indicated by the decrease in the surface negative charge (from -35 ± 1 mV to -30 ± 0.5 mV). Cellular studies demonstrated that LicpHA Rutin significantly reduced cell death and inflammation when compared to epirubicin alone. The levels of intracellular NLRP3, Myd-88, and proinflammatory cytokines were significantly lower in epirubicin + LicpHA Rutin-exposed cells when compared to epirubicin groups ( < 0.001). Hyaluronic acid-based nanoparticles loaded with Rutin exerts significant vasculo-protective properties during exposure to anthracyclines. The overall picture of this study pushes towards preclinical and clinical studies in models of anthracycline-induced vascular damages.
基于蒽环类药物的疗法通过过氧化作用和促炎细胞因子的产生对内皮细胞造成损伤，导致癌症患者发生心血管并发症的风险很高。基于透明质酸的混合纳米颗粒（LicpHA）是有效的药理学工具，可靶向内皮细胞并递送药物或营养保健品。本研究旨在制备并表征一种负载芦丁的新型LicpHA（LicpHA芦丁），芦丁是一种具有高抗氧化和抗炎特性的黄酮类化合物，用于保护内皮细胞免受表柔比星介导的内皮损伤。LicpHA芦丁采用磷脂酰胆碱、胆固醇、泊洛沙姆和透明质酸通过改良的纳米沉淀技术制备。对纳米颗粒进行了化学物理表征（尺寸、zeta电位、形态、稳定性、热分析和包封率）。在单独暴露于表柔比星或与游离芦丁或LicpHA芦丁联合暴露的人内皮细胞中进行了细胞毒性研究。通过使用选择性ELISA方法对NLRP-3、MyD-88、IL-1β、IL-6、IL17-α、TNF-α、IL-10和IL-4进行细胞内定量来进行抗炎研究。通过TEM和图像分析进行的形态学研究突出显示LicpHA颗粒群体具有非球形的异质性（圆度等于0.78±0.14），并且颗粒大小受芦丁包封的影响较小（平均直径从179±4nm变化到209±4nm）。热分析和zeta电位分析证实了芦丁对LicpHA芦丁化学物理性质的影响，主要表现为表面负电荷的减少（从-35±1mV降至-30±0.5mV）。细胞研究表明，与单独使用表柔比星相比，LicpHA芦丁可显著降低细胞死亡和炎症。与表柔比星组相比，暴露于表柔比星+LicpHA芦丁的细胞中细胞内NLRP3、Myd-88和促炎细胞因子的水平显著降低（<0.001）。负载芦丁的基于透明质酸的纳米颗粒在暴露于蒽环类药物期间具有显著的血管保护特性。这项研究的整体情况推动了在蒽环类药物诱导的血管损伤模型中的临床前和临床研究。
