Hybrid nanoparticles improve targeting to inflammatory macrophages through phagocytic signals.
Hybrid nanoparticles improve targeting to inflammatory macrophages through phagocytic signals.
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DOI：
10.1016/j.jconrel.2015.09.027
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发表时间：
2015-11-10
期刊：
影响因子：
--
通讯作者：
Maiseyeu A
中科院分区：
文献类型：
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作者：
Bagalkot V;Badgeley MA;Kampfrath T;Deiuliis JA;Rajagopalan S;Maiseyeu A
巨噬细胞是具有巨大表型可塑性的先天免疫细胞，这使得它们能够调节一系列生理过程，如宿主防御，组织修复和脂质/脂蛋白代谢。在这项原理验证研究中，我们报告了M1炎性表型的巨噬细胞可以被具有吞噬信号的模型混合脂质-乳胶（LiLa）纳米颗粒选择性地靶向。我们展示了一种简单而强大的路线来制造纳米颗粒，然后通过成像和药物递送在动脉粥样硬化和肥胖的炎症性疾病模型中显示其功效。自组装的LiLa纳米颗粒可以用各种疏水实体如药物货物、信号脂质和成像报告物进行修饰，从而产生具有低多分散性的亚100 nm纳米颗粒。具有钆、荧光素和“eat-me”吞噬信号的优化治疗诊断LiLa制剂（Gd-FITC-LiLa）a）表现出提高磁共振成像（MRI）灵敏度的高弛豫率，B）以高达60重量%包封疏水性药物，和c）选择性靶向炎性M1巨噬细胞，同时控制释放抗炎药物的有效载荷。有效载荷放电的机制和动力学似乎是磷脂酶A2活性依赖性的，通过细胞内Förster共振能量转移（FRET）的手段确定。在体内，LiLa靶向动脉粥样硬化小鼠模型中的M1巨噬细胞，允许通过MRI对动脉粥样硬化斑块进行非侵入性成像。在肥胖症的背景下，LiLa颗粒选择性地沉积到发炎脂肪组织内的M1巨噬细胞，如小鼠单光子活体成像所示。总的来说，我们的研究结果表明，吞噬信号可以优先靶向动脉粥样硬化和肥胖症的实验模型中的炎症巨噬细胞，从而打开了未来诊断/治疗这些疾病的临床应用的可能性。本文报道的可调LiLa纳米颗粒可以作为模型治疗诊断平台，应用于各种类型的疾病成像，如心血管疾病，肥胖症和巨噬细胞发挥致病作用的癌症。
Macrophages are innate immune cells with great phenotypic plasticity, which allows them to regulate an array of physiological processes such as host defense, tissue repair, and lipid/lipoprotein metabolism. In this proof-of-principle study, we report that macrophages of the M1 inflammatory phenotype can be selectively targeted by model hybrid lipid–latex (LiLa) nanoparticles bearing phagocytic signals. We demonstrate a simple and robust route to fabricate nanoparticles and then show their efficacy through imaging and drug delivery in inflammatory disease models of atherosclerosis and obesity. Self-assembled LiLa nanoparticles can be modified with a variety of hydrophobic entities such as drug cargos, signaling lipids, and imaging reporters resulting in sub-100 nm nano-particles with low polydispersities. The optimized theranostic LiLa formulation with gadolinium, fluorescein and “eat-me” phagocytic signals (Gd-FITC-LiLa) a) demonstrates high relaxivity that improves magnetic resonance imaging (MRI) sensitivity, b) encapsulates hydrophobic drugs at up to 60% by weight, and c) selectively targets inflammatory M1 macrophages concomitant with controlled release of the payload of anti-inflammatory drug. The mechanism and kinetics of the payload discharge appeared to be phospholipase A2 activity-dependent, as determined by means of intracellular Förster resonance energy transfer (FRET). In vivo, LiLa targets M1 macrophages in a mouse model of atherosclerosis, allowing noninvasive imaging of atherosclerotic plaque by MRI. In the context of obesity, LiLa particles were selectively deposited to M1 macrophages within inflamed adipose tissue, as demonstrated by single-photon intravital imaging in mice. Collectively, our results suggest that phagocytic signals can preferentially target inflammatory macrophages in experimental models of atherosclerosis and obesity, thus opening the possibility of future clinical applications that diagnose/treat these conditions. Tunable LiLa nanoparticles reported here can serve as a model theranostic platform with application in various types of imaging of the diseases such as cardiovascular disorders, obesity, and cancer where macrophages play a pathogenic role.