Tumor‐Specific Self‐Degradable Nanogels as Potential Carriers for Systemic Delivery of Anticancer Proteins,Advanced Functional Materials

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Tumor‐Specific Self‐Degradable Nanogels as Potential Carriers for Systemic Delivery of Anticancer Proteins
Advanced Functional Materials ( IF 18.5 ) Pub Date : 2018-02-19 , DOI: 10.1002/adfm.201707371
Qiuwen Zhu ₁ , Xiaojie Chen ₁ , Xiao Xu ₁ , Ying Zhang ₁ , Can Zhang ₁ , Ran Mo ₁

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Development of a safe and effective carrier for systemic protein delivery is highly desirable, which depends on management of the relationship among loading capacity, stability, delivery efficiency, and degradability. Here, a tumor‐specific self‐degradable nanogel composed of hyaluronidase (HAase)‐degradable hyaluronic acid (HA) matrices entrapping acid‐activatable HAase (aHAase) for systemic delivery of anticancer proteins is reported. Collaboratively crosslinked nanogels (cNG) obtained by the synthetic cholesteryl methacrylated HA show high protein‐loading capacity and stability. The aHAase is engineered by modifying the HAase with citraconic anhydride to shield its HA‐degrading activity, which can be reversibly activated by hydrolysis of the citraconic amide under acidic condition. In the tumor microenvironment, the mild acidity activates the aHAase partially, which results in swelling of the cNG and releasing of the aHAase. The released reactivated aHAase can degrade the HA that is also a major constituent of tumor extracellular matrix to increase perfusion of the cNG in the tumor stroma. In the acidic endocytic vesicles, the aHAase is fully reactivated. The active aHAase completely degrades the cNG to release the encapsulated anticancer protein, deoxyribonuclease I intracellularly, which digests the DNA to cause tumor cell death for enhanced antitumor efficacy.

中文翻译：

肿瘤特异性自降解纳米凝胶作为系统递送抗癌蛋白的潜在载体

迫切需要开发安全有效的用于全身性蛋白质递送的载体，这取决于对装载量，稳定性，递送效率和可降解性之间关系的管理。在这里，报道了一种由透明质酸酶（HAase）-可降解透明质酸（HA）基质组成的肿瘤特异性可自降解纳米凝胶，其中包埋了可酸激活的HAase（aHAase），用于系统递送抗癌蛋白。合成的甲基丙烯酸胆固醇酯化HA获得的协同交联的纳米凝胶（cNG）具有很高的蛋白质负载能力和稳定性。通过用柠康酸酐修饰HAase以保护其HA降解活性来设计aHAase，在酸性条件下，柠康酰胺水解可逆地激活HAHAase。在肿瘤微环境中温和的酸性会部分激活aHAase，导致cNG溶胀并释放aHAase。释放的重新活化的aHAase可以降解HA，它也是肿瘤细胞外基质的主要成分，以增加cNG在肿瘤基质中的灌注。在酸性内吞囊泡中，aHAase被完全重新激活。活性aHAase完全降解cNG，在细胞内释放封装的抗癌蛋白脱氧核糖核酸酶I，该酶消化DNA导致肿瘤细胞死亡，从而增强抗肿瘤功效。aHAase被完全重新激活。活性aHAase完全降解cNG，在细胞内释放封装的抗癌蛋白脱氧核糖核酸酶I，该酶消化DNA导致肿瘤细胞死亡，从而增强抗肿瘤功效。aHAase被完全重新激活。活性aHAase完全降解cNG，在细胞内释放封装的抗癌蛋白脱氧核糖核酸酶I，该酶消化DNA导致肿瘤细胞死亡，从而增强抗肿瘤功效。

更新日期：2018-02-19

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