Targeted Therapy for Acute Autoimmune Myocarditis with Nano-Sized Liposomal FK506 in Rats.
Targeted Therapy for Acute Autoimmune Myocarditis with Nano-Sized Liposomal FK506 in Rats.
复制标题
DOI：
10.1371/journal.pone.0160944
复制
发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Minamino T
中科院分区：
文献类型：
--
作者：
Okuda K;Fu HY;Matsuzaki T;Araki R;Tsuchida S;Thanikachalam PV;Fukuta T;Asai T;Yamato M;Sanada S;Asanuma H;Asano Y;Asakura M;Hanawa H;Hao H;Oku N;Takashima S;Kitakaze M;Sakata Y;Minamino T
免疫抑制剂用于治疗免疫介导的心肌炎;然而，仍然需要开发更有效的治疗方法。纳米尺寸的脂质体可以在具有增强的血管渗透性的炎性病变中积聚并选择性地将药物递送至炎性病变。本研究的目的是研究FK 506脂质体，一种免疫抑制剂包裹在脂质体中的分布，以及药物对大鼠实验性自身免疫性心肌炎（EAM）模型心功能的影响。我们制备了聚乙二醇修饰的FK 506脂质体（平均粒径：109.5 ± 4.4 nm）。我们通过猪肌球蛋白免疫诱导了EAM，并评估了该模型中纳米珠和脂质体FK 506的组织分布。在免疫后第14天和第17天给予脂质体或游离FK 506后，在第21天测定大鼠心脏中的细胞因子表达沿着组织学发现和血流动力学参数。离体荧光成像显示，静脉内施用的荧光标记的纳米大小的珠粒在免疫后第14天和此后在心肌炎但不是正常心脏中积累。与游离FK 506给药相比，给予FK 506脂质体后，EAM大鼠血浆和心脏中的FK 506水平均升高。与游离FK 506相比，FK 506脂质体给药可显著抑制细胞因子（如干扰素-γ和肿瘤坏死因子-α）的表达，并减少第21天心肌中的炎症和纤维化。与游离FK 506相比，FK 506脂质体给药也显著改善了第21天的心功能障碍。纳米脂质体有望成为心肌保护剂靶向给药系统。
Immunosuppressive agents are used for the treatment of immune-mediated myocarditis; however, the need to develop a more effective therapeutic approach remains. Nano-sized liposomes may accumulate in and selectively deliver drugs to an inflammatory lesion with enhanced vascular permeability. The aims of this study were to investigate the distribution of liposomal FK506, an immunosuppressive drug encapsulated within liposomes, and the drug’s effects on cardiac function in a rat experimental autoimmune myocarditis (EAM) model. We prepared polyethylene glycol-modified liposomal FK506 (mean diameter: 109.5 ± 4.4 nm). We induced EAM by immunization with porcine myosin and assessed the tissue distribution of the nano-sized beads and liposomal FK506 in this model. After liposomal or free FK506 was administered on days 14 and 17 after immunization, the cytokine expression in the rat hearts along with the histological findings and hemodynamic parameters were determined on day 21. Ex vivo fluorescent imaging revealed that intravenously administered fluorescent-labeled nano-sized beads had accumulated in myocarditic but not normal hearts on day 14 after immunization and thereafter. Compared to the administration of free FK506, FK506 levels were increased in both the plasma and hearts of EAM rats when liposomal FK506 was administered. The administration of liposomal FK506 markedly suppressed the expression of cytokines, such as interferon-γ and tumor necrosis factor-α, and reduced inflammation and fibrosis in the myocardium on day 21 compared to free FK506. The administration of liposomal FK506 also markedly ameliorated cardiac dysfunction on day 21 compared to free FK506. Nano-sized liposomes may be a promising drug delivery system for targeting myocarditic hearts with cardioprotective agents.