QCM-D Investigations on Cholesterol-DNA Tethering of Liposomes to Microbubbles for Therapy.
QCM-D Investigations on Cholesterol-DNA Tethering of Liposomes to Microbubbles for Therapy.
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DOI：
10.1021/acs.jpcb.2c07256
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发表时间：
2023-03-23
影响因子：
3.3
通讯作者：
Evans, Stephen D.
中科院分区：
文献类型：
--
作者：
Armistead, Fern J.;Batchelor, Damien V. B.;Johnson, Benjamin R. G.;Evans, Stephen D.
脂质壳微泡（MB）具有作为治疗诊断剂的潜力，能够增强超声成像的对比度，并提供触发药物释放和改善局部药物输送的途径。此类治疗载体设计中的一个常见主题是将药物载体（通常以脂质体的形式）附着到微泡上。传统上，此类附着物基于生物素-链霉亲和素和马来酰亚胺-PDP 化学物质。相比之下，DNA-脂质系链的使用具有潜在的优势。首先，它们的特异性允许构建更复杂的结构，其中可能包括不同载药脂质体和/或靶向基团（例如仿射体或抗体）的定制组合。其次，使用双脂质系链策略应该增加将脂质体系到气泡上的各个系链的强度。胆固醇-DNA (cDNA) 系链将脂质体缀合到支持的脂质双层的能力先前已被证明。对于体内应用，气泡和脂质体通常含有一定比例的聚乙二醇 (PEG)，以促进隐形特性并延长使用寿命。然而，相关的空间效应可能会阻碍药物有效负载的束缚。我们表明，虽然 PEG 的存在降低了束缚亲和力，但 cDNA 仍可用于将脂质体附着到支持的脂质双层 (SLB)（通过 QCM-D 测量）。重要的是，我们首次表明，QCM-D 可用于使用 cDNA 研究微泡与 SLB 的束缚，与单独的脂质体相比，由于 MB 密度降低，频移幅度减小。然后，我们大量复制这种束缚相互作用，并观察脂质体附着在中央 MB 的外壳上，从而形成模型治疗微泡。
Lipid-shelled microbubbles (MBs) offer potential as theranostic agents, capable of providing both contrast enhancement in ultrasound imaging as well as a route for triggered drug release and improved localized drug delivery. A common motif in the design of such therapeutic vehicles is the attachment of the drug carrier, often in the form of liposomes, to the microbubble. Traditionally, such attachments have been based around biotin–streptavidin and maleimide–PDP chemistries. Comparatively, the use of DNA–lipid tethers offers potential advantage. First, their specificity permits the construction of more complex architectures that might include bespoke combinations of different drug-loaded liposomes and/or targeting groups, such as affimers or antibodies. Second, the use of dual-lipid tether strategies should increase the strength of the individual tethers tethering the liposomes to the bubbles. The ability of cholesterol–DNA (cDNA) tethers for conjugation of liposomes to supported lipid bilayers has previously been demonstrated. For in vivo applications, bubbles and liposomes often contain a proportion of polyethylene glycol (PEG) to promote stealth-like properties and increase lifetimes. However, the associated steric effects may hinder tethering of the drug payload. We show that while the presence of PEG reduced the tethering affinity, cDNA can still be used for the attachment of liposomes to a supported lipid bilayer (SLB) as measured via QCM-D. Importantly, we show, for the first time, that QCM-D can be used to study the tethering of microbubbles to SLBs using cDNA, signified by a decrease in the magnitude of the frequency shift compared to liposomes alone due to the reduced density of the MBs. We then replicate this tethering interaction in the bulk and observe attachment of liposomes to the shell of a central MB and hence formation of a model therapeutic microbubble.
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