Grimsley Lauren B, West Phillip C, McAdams Callie D, Bush Charles A, Kirkpatrick Stacy S, Arnold Joshua D, Buckley Michael R, Dieter Raymond A, Freeman Michael B, McNally Michael M, Stevens Scott L, Grandas Oscar H, Mountain Deidra J H
Department of Surgery, University of Tennessee Graduate School of Medicine, 1924 Alcoa Highway Box U-11, Knoxville, TN 37920, USA.
Pharmaceutics. 2021 Oct 31;13(11):1816. doi: 10.3390/pharmaceutics13111816.
Vascular interventions result in the disruption of the tunica intima and the exposure of sub-endothelial matrix proteins. Nanoparticles designed to bind to these exposed matrices could provide targeted drug delivery systems aimed at inhibiting dysfunctional vascular remodeling and improving intervention outcomes. Here, we present the progress in the development of targeted liposomal nanocarriers designed for preferential collagen IV binding under simulated static vascular flow conditions. PEGylated liposomes (PLPs), previously established as effective delivery systems in vascular cells types, served as non-targeting controls. Collagen-targeting liposomes (CT-PLPs) were formed by conjugating established collagen-binding peptides to modified lipid heads via click chemistry (CTL), and inserting them at varying mol% either at the time of PLP assembly or via micellar transfer. All groups included fluorescently labeled lipid species for imaging and quantification. Liposomes were exposed to collagen IV matrices statically or via hemodynamic flow, and binding was measured via fluorometric analyses. CT-PLPs formed with 5 mol% CTL at the time of assembly demonstrated the highest binding affinity to collagen IV under static conditions, while maintaining a nanoparticle characterization profile of ~50 nm size and a homogeneity polydispersity index (PDI) of ~0.2 favorable for clinical translation. When liposomes were exposed to collagen matrices within a pressurized flow system, empirically defined CT-PLPs demonstrated significant binding at shear stresses mimetic of physiological through pathological conditions in both the venous and arterial architectures. Furthermore, when human saphenous vein explants were perfused with liposomes within a closed bioreactor system, CT-PLPs demonstrated significant ex vivo binding to diseased vascular tissue. Ongoing studies aim to further develop CT-PLPs for controlled targeting in a rodent model of vascular injury. The CT-PLP nanocarriers established here show promise as the framework for a spatially controlled delivery platform for future application in targeted vascular therapeutics.
血管介入会导致内膜层破坏以及内皮下基质蛋白暴露。设计用于结合这些暴露基质的纳米颗粒可提供靶向给药系统，旨在抑制功能失调的血管重塑并改善介入治疗效果。在此，我们展示了在模拟静态血管流动条件下设计用于优先结合IV型胶原的靶向脂质体纳米载体的研发进展。聚乙二醇化脂质体（PLP）此前已被确立为血管细胞类型中的有效递送系统，用作非靶向对照。通过点击化学（CTL）将已确立的胶原结合肽与修饰的脂质头部偶联，并在PLP组装时或以不同摩尔百分比通过胶束转移插入，从而形成胶原靶向脂质体（CT-PLP）。所有组均包含用于成像和定量的荧光标记脂质种类。脂质体静态或通过血流动力学流动暴露于IV型胶原基质，通过荧光分析测量结合情况。在组装时由5摩尔％的CTL形成的CT-PLP在静态条件下对IV型胶原表现出最高的结合亲和力，同时保持约50纳米大小的纳米颗粒表征轮廓和约0.2的均一性多分散指数（PDI），有利于临床转化。当脂质体在加压流动系统中暴露于胶原基质时，经验性定义的CT-PLP在模拟生理到病理条件的剪切应力下，在静脉和动脉结构中均表现出显著结合。此外，当在封闭的生物反应器系统中用人隐静脉外植体灌注脂质体时，CT-PLP在体外对病变血管组织表现出显著结合。正在进行的研究旨在进一步开发CT-PLP，用于在血管损伤的啮齿动物模型中进行可控靶向。在此建立的CT-PLP纳米载体有望作为空间可控递送平台的框架，用于未来的靶向血管治疗。
