Lipid-shelled vehicles: engineering for ultrasound molecular imaging and drug delivery.
Lipid-shelled vehicles: engineering for ultrasound molecular imaging and drug delivery.
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DOI：
10.1021/ar8002442
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发表时间：
2009-07-21
影响因子：
18.3
通讯作者：
Zhang, Hua
中科院分区：
文献类型：
--
作者：
Ferrara, Katherine W.;Borden, Mark A.;Zhang, Hua
超声压力波可以映射脂质稳定的气体微泡在体内静脉给药后的位置，便于估计血管密度和微血管流速。目前，美国食品和药物管理局批准微泡作为超声造影剂，用于超声心动图中左心室的显影。然而，超声波与静脉注射的脂质壳颗粒（包括脂质体和微泡）的相互作用是一个更丰富的领域。粒子可以被设计用于分子成像，并装载药物或基因超声的机械和热特性可以影响局部药物释放。在本报告中，我们概述了脂质壳微泡（典型直径为1000- 10，000 nm）和脂质体（典型直径为65-120 nm）在分子成像和药物输送中基于超声的应用。可以优化壳和核的化学性质以增强稳定性、循环持久性、药物装载和释放、靶向细胞膜并与细胞膜融合以及治疗性生物效应。为了评估这些颗粒的生物分布和药代动力学，我们将正电子发射断层扫描（PET）放射性同位素的外壳。将放射性核素18 F（半衰期约2小时）共价偶联至二棕榈酰脂质，然后将标记脂质整合至壳中，便于对颗粒药代动力学和脂质分子代谢进行短期分析。或者，在将铜螯合部分共价结合到脂质壳上之后，用64 Cu（半衰期12.7小时）标记形成的颗粒允许在几天内对颗粒进行药代动力学研究。脂质体和微泡在循环中的稳定性和持久性通过长酰基链和聚乙二醇涂层来增强。血管靶向已经用纳米直径和微米直径的颗粒证明。微泡的靶向亲和力可以通过将配体埋在聚合物刷层内来调节;然后应用超声波揭示配体，从而仅能够特异性靶向声穿透区域。微泡和脂质体需要不同的药物装载和释放策略。微泡装载被气体核心抑制，并通过逐层构造或药物包埋颗粒与表面的缀合而增强。脂质体装载通常是内部的，并且通过药物特异性装载技术来增强。药物从微泡中的释放是由声波产生的气核直径的振荡引起的，而从脂质体中的药物释放是由组织微环境内声能的局部吸收产生的热量增强的。超声引起的生物学效应，如细胞膜和血管通透性的变化，可以增强药物的释放。特别地，当微泡在血管壁附近振荡时，冲击波或液体射流增强药物输送。在注射药物之前或之后，由超声诱导的温和加热促进脂质体从血管运输到组织脂质体，从而增加靶区域中的药物蓄积。脂壳载体为化学家和工程师提供了许多机会;随着分子构建技术的进一步完善，除了目前常用的几种之外，基于超声的应用无疑将很快成倍增加。
Ultrasound pressure waves can map the location of lipid-stabilized gas microbubbles after their intravenous administration in the body, facilitating an estimate of vascular density and microvascular flow rate. Microbubbles are currently approved by the Food and Drug Administration as ultrasound contrast agents for visualizing opacification of the left ventricle in echocardiography. However, the interaction of ultrasound waves with intravenously injected lipid-shelled particles, including both liposomes and microbubbles, is a far richer field. Particles can be designed for molecular imaging and loaded with drugs or genes—the mechanical and thermal properties of ultrasound can then effect localized drug release. In this Account, we provide an overview of the engineering of lipid-shelled microbubbles (typical diameter 1000–10,000 nm) and liposomes (typical diameter 65–120 nm) for ultrasound-based applications in molecular imaging and drug delivery. The chemistries of the shell and core can be optimized to enhance stability, circulation persistence, drug loading and release, targeting to and fusion with the cell membrane, and therapeutic biological effects. To assess the biodistribution and pharmacokinetics of these particles, we incorporated positron emission tomography (PET) radioisotopes on the shell. The radionuclide 18F (half life ~2 hours) was covalently coupled to a dipalmitoyl lipid, followed by integration of the labeled lipid into the shell, facilitating short-term analysis of particle pharmacokinetics and metabolism of the lipid molecule. Alternately, labeling a formed particle with 64Cu (half life 12.7 hours)—after prior covalent incorporation of a copper-chelating moiety onto the lipid shell—permits pharmacokinetic study of particles over several days. Stability and persistence in circulation of both liposomes and microbubbles are enhanced by long acyl chains and a polyethylene glycol coating. Vascular targeting has been demonstrated with both nano- and micro-diameter particles. Targeting affinity of the microbubble can be modulated by burying the ligand within a polymer brush layer; the application of ultrasound then reveals the ligand, enabling specific targeting of only the insonified region. Microbubbles and liposomes require different strategies for both drug loading and release. Microbubble loading is inhibited by the gas core and enhanced by layer-by-layer construction or conjugation of drug-entrapped particles to the surface. Liposome loading is typically internal and is enhanced by drug-specific loading techniques. Drug release from a microbubble results from the oscillation of the gas core diameter produced by the sound wave, whereas that from a liposome is enhanced by heat produced from the local absorption of acoustic energy within the tissue microenvironment. Biological effects induced by ultrasound, such as changes in cell membrane and vascular permeability, can enhance drug delivery. In particular, as microbubbles oscillate near a vessel wall, shock waves or liquid jets enhance drug transport. Mild heating induced by ultrasound, either before or after injection of the drug, facilitates the transport of liposomes from blood vessels to the tissue interstitium, thus increasing drug accumulation in the target region. Lipid-shelled vehicles offer many opportunities for chemists and engineers; ultrasound-based applications beyond the few currently in common use will undoubtedly soon multiply as molecular construction techniques are further refined.
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