Kang Minjee, Huang Grace, Leal Cecilia
Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Soft Matter. 2014 Nov 28;10(44):8846-54. doi: 10.1039/c4sm01431f.
Ultrasound (US) triggered drug release is a promising drug delivery method that allows ex vivo modulation of treatment intensity and duration. This method relies on the synergistic interaction between the rupture of sonosensitive particles and enhanced plasma membrane permeability. Conventional liposomal systems where the drug passively diffuses through the membrane show virtually no response to acoustic energy. One method to activate drug transport is to induce a topological restructuring of the lipid membrane (zero intrinsic curvature, H = 0) by puncturing pores (H < 0) through which the drug can readily leak out from the interior of the liposomes. In this work we demonstrate strategies to lower the energy cost of creating such membrane defects by introducing lipid molecules with molecular shapes prone to self-assemble into non-lamellar (negative intrinsic curvature, H < 0) structures. All formulations investigated comprise the relevant components typically required for delivery applications such as stealth moieties, cholesterol, and phospholipids. Small angle X-ray scattering studies of a number of lipid systems at increasing amounts of phosphatidylethanolamine (PE) phospholipids reveal that membranes without PE respond to ultrasound by thinning ca. 10 Å, which concomitantly lowers the bending rigidity quadratically in addition to increasing the passive drug permeability. However, at the appropriate PE content the lipid systems display a classic lamellar structure (H = 0) that undergoes a topological transformation after ultrasound exposure into lipid tubes of the reversed type (H < 0) packed in a 2D hexagonal array. At the dilute regime, Fluorescence Microscopy of giant unilamellar vesicles (GUVs) comprising DOPE also experience ultrasound induced restructuring that can be modulated by DOPE content. In general, smaller vesicles of diverse shape connect and form into a "pearl-necklace" configuration. We argue that the inclusion of DOPE within the GUV membrane may result in curvature-driven lipid sorting, providing the system with local membrane instabilities that drive vesicle pearling when exposed to ultrasound.
超声（US）触发药物释放是一种很有前景的药物递送方法，它能够在体外调节治疗强度和持续时间。该方法依赖于声敏颗粒破裂与增强的质膜通透性之间的协同相互作用。药物通过膜被动扩散的传统脂质体系统对声能几乎没有反应。一种激活药物转运的方法是通过刺穿孔隙（H < 0）来诱导脂质膜的拓扑结构重组（零固有曲率，H = 0），药物可通过这些孔隙从脂质体内部轻易泄漏出来。在这项工作中，我们展示了通过引入分子形状易于自组装成非层状（负固有曲率，H < 0）结构的脂质分子来降低产生此类膜缺陷的能量成本的策略。所有研究的制剂都包含递送应用通常所需的相关成分，如隐身部分、胆固醇和磷脂。对多种含有不同量磷脂酰乙醇胺（PE）磷脂的脂质系统进行的小角X射线散射研究表明，不含PE的膜在超声作用下变薄约10 Å，这除了增加被动药物通透性外，还会使弯曲刚度二次降低。然而，在适当的PE含量下，脂质系统呈现出经典的层状结构（H = 0），在超声暴露后会经历拓扑转变，形成二维六边形阵列排列的反向型脂质管（H < 0）。在稀释状态下，包含二油酰磷脂酰乙醇胺（DOPE）的巨型单层囊泡（GUVs）的荧光显微镜观察也显示超声诱导的重组，其可由DOPE含量调节。一般来说，各种形状的较小囊泡会连接并形成“珍珠项链”构型。我们认为，在GUV膜中包含DOPE可能会导致曲率驱动的脂质分选，为系统提供局部膜不稳定性，使其在暴露于超声时驱动囊泡成珠。
