A Multitheragnostic Nanobubble System to Induce Blood-Brain Barrier Disruption with Magnetically Guided Focused Ultrasound
A Multitheragnostic Nanobubble System to Induce Blood-Brain Barrier Disruption with Magnetically Guided Focused Ultrasound
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DOI：
10.1002/adma.201403889
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发表时间：
2015-01-27
影响因子：
29.4
通讯作者：
Chen, You-Yin
中科院分区：
文献类型：
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作者：
Huang, Hsin-Yang;Liu, Hao-Li;Chen, You-Yin
DOI：10.1002/adma. 201403889，因为它们可以穿透肿瘤血管孔进行靶向成像。[7]与微米尺寸的气泡相比，MNB固有地提供相对低的US散射效率，使得难以诱导足够的声空化活动以成功地破坏BBB。[8]最近，已经努力开发新的结构化气泡以促进微流并增强内皮渗透性[9]或局部增加气泡浓度以产生足够的活性空化。[10]使用纳米尺寸的气泡来诱导BBB破坏，同时对体内脑组织造成最小的损伤，仍然非常具有挑战性。因此，我们假设，通过设计新的磁引导（MG）MNB和采用磁引导，以积极增加局部纳米气泡浓度，它可以使成功的血脑屏障破坏安全的脑药物输送或治疗。在这项研究中，我们合成了MG治疗诊断MNBs与双模态对比，同时进行FUS诱导的BBB破坏和MRI/US双模态造影剂成像，通过嵌入超顺磁性氧化铁（SPIO）纳米粒子在二氧化硅壳MNBs.As方案1中所示，所提出的MNBs有可能成为有效的US造影剂和优秀的MR敏感性造影剂。有趣的是，这与先前关于使用基于脂质和微米尺寸的气泡而不是提出的基于磁性二氧化硅的纳米尺寸气泡破坏BBB的报道[11]不同。这种情况下的一个关键特征是双靶向方案; MNB首先通过外部磁场磁性引导到非靶侧，然后使用FUS暴露来局部破坏靶向BBB。累积的MNB可以增加BBB破坏效率，并通过累积的MG引导的MNB增强US和MR成像对比度强度。图1示出了MNB的合成过程。我们制造了具有单分散分布的起泡剂，以提供最大的激发效率。聚苯乙烯（PS）颗粒被用作核心模板，以形成亚微米尺寸的MNB。为了调节壳性质，包括壳刚度、孔隙率和亲水性，使用辛基三乙氧基硅烷（OTES）、原硅酸四乙酯（TEOS）和（3-氨基丙基）三乙氧基硅烷（APTES）（图1a）。首先，通过来自油酸缀合的有机亲和力将OTES附着到SPIO表面是修饰表面电荷的关键步骤，导致OTES修饰的SPIO纳米颗粒可以容易地静电附着到带正电荷的PS核心颗粒（如图1 B中所示）。测量了OTES修饰的SPIO纳米颗粒的zeta电位
DOI: 10.1002/adma. 201403889 because they can penetrate tumor blood vessel pores for targeted imaging.[7] MNBs intrinsically provide a relatively low US scattering efficiency in comparison to micrometer-sized bubbles, making it difficult to induce enough acoustic cavitation activity to successfully disrupt the BBB.[8] Recently, there have been efforts to develop new structured bubbles to promote microstreaming and enhance the endothelium permeability [9] or to locally increase bubble concentration to produce sufficient activity cavitation.[10] It is still very challenging to use nanometer-sized bubbles to induce BBB disruption with minimal damage to brain tissue in vivo. We therefore hypothesized that by designing novel magnetically guidable (MG) MNBs and employing magnetic guidance to actively increase the local nanobubble concentration, it may enable successful BBB disruption for secure brain drug delivery or therapy. In this study, we synthesized MG theranostic MNBs with dual-modality contrast to concurrently perform FUS-induced BBB disruption and MRI/US dual-modality contrast agent imaging by embedding the super-paramagnetic iron oxide (SPIO) nanoparticles in a silica shell in MNBs.As illustrated in Scheme 1, the proposed MNBs have the potential to become effective US contrast agents and excellent MR susceptibility contrast agents. Interestingly, this is distinct from previous reports [11] on BBB disruption with lipid-based and micrometer-sized bubbles instead of the proposed magnetically silica-based nanometer-sized bubbles. A key feature in this case is the double-targeting scenario; MNBs are first magnetically guided to the nontarget side by an external magnetic field and then FUS exposure is used to locally disrupt the targeted BBB. The accumulated MNBs can increase the BBB disruption efficiency and enhance both US and MR imaging contrast intensity through accumulated MG-guided MNBs. Figure 1 illustrates the synthesis process for MNBs. We fabricated the bubble agents with a monodispersed distribution to provide maximum excitation efficiency. Polystyrene (PS) particles were used as a core template to form the sub-micrometer-sized MNBs. To adjust the shell properties, including the shell stiffness, porosity, and hydrophilicity, octyltriethoxysilane (OTES), tetraethyl orthosilicate (TEOS), and (3-aminopropyl) triethoxysilane (APTES) were used (Figure 1 a). First, the attachment of OTES to the SPIO surface through the organic affinity from the oleic acid conjugation was the key step to modify the surface charge, leading to OTES-modified SPIO nanoparticles that can be easily electrostatically attached to the positively charged PS core particles (shown in Figure 1 b). The zeta potential of the OTES-modified SPIO nanoparticles was measured