Ultrasound Facilitates Naturally Equipped Exosomes Derived from Macrophages and Blood Serum for Orthotopic Glioma Treatment
Ultrasound Facilitates Naturally Equipped Exosomes Derived from Macrophages and Blood Serum for Orthotopic Glioma Treatment
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DOI：
10.1021/acsami.9b00893
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发表时间：
2019-04-24
影响因子：
9.5
通讯作者：
Wang, Xiaobing
中科院分区：
文献类型：
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作者：
Bai, Lianmei;Liu, Yichen;Wang, Xiaobing
外切体(Exosome，Exos)是内源性纳米载体，可作为治疗脑癌的新型递送系统。然而，通常情况下，天然Exos显示出有限的BBB跨越能力，并且缺乏特定的靶向性。进一步的修改，包括靶向多肽和基因工程方法，可以绕过这些问题，但这个过程是耗时的。聚焦超声(FUS)因其无创性、可逆性和瞬间局部开放血脑屏障而被美国食品和药物管理局批准用于脑部疾病的诊断和治疗。在这项研究中，我们开发了一种使用FUS的自然和安全的运输系统，以增加胶质瘤治疗中外源性OS的靶向性输送。我们还比较了巨噬细胞来源的Exos(R-Exos)和血清来源的Exos(B-Exos)的优势，以筛选出具有临床转化空间的改进平台。在体外，R-Exos和B-Exos均通过BBB模型转运，并在超声作用下在胶质瘤细胞内蓄积。与FUS联合应用时，R-Exos和B-Exos在物理性质、药物释放、肿瘤靶向性和细胞毒性等方面无明显差异。活体动物成像研究表明，B-Exos加单一FUS在脑内的荧光强度是单独使用B-Exos的4.45倍。此外，B-Exos加两次FUS治疗有效地抑制了胶质瘤的生长，且没有明显的副作用。因此，我们证明FUS和天然丰富的B-Exos的结合是脑癌治疗的一种有效策略。
Exosomes (Exos) are endogenous nanocarriers that have utility as novel delivery systems for the treatment of brain cancers. However, in general, natural Exos show limited BBB-crossing capacity and lack specific targeting. Further modifications including targeting peptides and genetic engineering approaches can circumvent these issues, but the process is time-consuming. Focused ultrasound (FUS) has been approved by the Food and Drug Administration for the diagnosis and treatment of brain diseases due to its noninvasive nature, reversibility, and instantaneous local opening of the BBB. In this study, we developed a natural and safe transportation system using FUS to increase the targeted delivery of Exos for glioma therapy. We also compared the advantages of macrophage-derived Exos (R-Exos) and blood serum-derived Exos (B-Exos) to screen for an improved platform with scope for clinical transformation. In vitro, both R-Exos and B-Exos were transported through BBB models and accumulated in glioma cells with the assistance of ultrasound exposure. R-Exos and B-Exos displayed no obvious differences in physical characteristics, drug release, tumor targeting, and cytotoxicity when combined with FUS. In vivo animal imaging studies suggested that the fluorescence intensity of B-Exos plus single FUS in brains was 4.45-fold higher than that of B-Exos alone. Furthermore, B-Exos plus twice FUS treatment efficiently suppressed glioma growth with no obvious side effects. We therefore demonstrate that the combination of FUS and naturally abundant B-Exos is a potent strategy for brain cancer therapeutics.