Exosome as a Vehicle for Delivery of Membrane Protein Therapeutics, PH20, for Enhanced Tumor Penetration and Antitumor Efficacy
Exosome as a Vehicle for Delivery of Membrane Protein Therapeutics, PH20, for Enhanced Tumor Penetration and Antitumor Efficacy
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DOI：
10.1002/adfm.201703074
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发表时间：
2018-01-31
影响因子：
19
通讯作者：
Kim, In-San
中科院分区：
文献类型：
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作者：
Hong, Yeonsun;Nam, Gi-Hoon;Kim, In-San
由于膜蛋白的生物化学和功能研究仍然是一个挑战，有越来越多的兴趣在应用纳米技术来解决开发膜蛋白治疗的困难。外泌体是由脂质双层包围的纳米级细胞外囊泡组成的，是提供天然膜组合物的成功平台。这项研究报告了一种酶外泌体，它含有天然的PH 20透明质酸酶（Exo-PH 20），能够通过透明质酸降解深入渗透到肿瘤病灶中，从而抑制肿瘤生长并增加T细胞浸润到肿瘤中。开发这种基于外泌体的策略以克服免疫抑制和抗癌治疗抗性肿瘤微环境，其特征在于过度积累的细胞外基质。值得注意的是，这种具有天然糖基磷脂酰肌醇锚定形式的透明质酸酶的工程化外泌体具有比截短形式的重组蛋白更高的酶活性。此外，外泌体介导的PH 20透明质酸酶和化疗剂（多柔比星）的共递送有效地抑制肿瘤生长。这种外泌体被设计为降解透明质酸，从而增强纳米颗粒渗透和药物扩散。因此，结果表明，这是一种有前途的基于外泌体的平台，其不仅具有高活性的膜相关酶，而且具有治疗有效载荷。
As biochemical and functional studies of membrane protein remain a challenge, there is growing interest in the application of nanotechnology to solve the difficulties of developing membrane protein therapeutics. Exosome, composed of lipid bilayer enclosed nanosized extracellular vesicles, is a successful platform for providing a native membrane composition. This study reports an enzymatic exosome, which harbors native PH20 hyaluronidase (Exo-PH20), which is able to penetrate deeply into tumor foci via hyaluronan degradation, allowing tumor growth inhibition and increased T cell infiltration into the tumor. This exosome-based strategy is developed to overcome the immunosuppressive and anticancer therapy-resistant tumor microenvironment, which is characterized by an overly accumulated extracellular matrix. Notably, this engineered exosome with the native glycosylphosphatidylinositol-anchored form of hyaluronidase has a higher enzymatic activity than a truncated form of the recombinant protein. In addition, the exosome-mediated codelivery of PH20 hyaluronidase and a chemotherapeutic (doxorubicin) efficiently inhibits tumor growth. This exosome is designed to degrade hyaluronan, thereby augmenting nanoparticle penetration and drug diffusion. The results thus show that this is a promising exosome-based platform that harbors not only a membrane-associated enzyme with high activity but also therapeutic payloads.