Micellar Thrombin-Binding Aptamers: Reversible Nanoscale Anticoagulants
Micellar Thrombin-Binding Aptamers: Reversible Nanoscale Anticoagulants
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DOI：
10.1021/jacs.7b07799
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发表时间：
2017-11-22
影响因子：
15
通讯作者：
Gianneschi, Nathan C.
中科院分区：
文献类型：
--
作者：
Roloff, Alexander;Carlini, Andrea S.;Gianneschi, Nathan C.
适配体是基于核酸的配体，具有特异性和可逆性的靶标结合和抑制作用。适配体可以作为抗凝血剂，如果他们是直接针对酶的凝血级联。然而，它们通常遭受溶核消化和快速从血液中清除。我们提出凝血酶结合适配体两亲体，自组装成纳米级聚合物胶束，具有密集功能化的适配体显示电晕。我们表明，这些胶束适体在拥挤的环境中保持其天然的二级结构，并在人血清中稳定地抵抗核酸酶的降解。此外，它们是体外有效的人血浆凝血抑制剂。这种抑制作用可以通过互补核酸在杂交时破坏适体的二级结构而迅速逆转。与游离适配体相比，整体装配体的分子量和大小的增加促进了体内血液循环时间的延长。
Aptamers are nucleic acid-based ligands that exhibit promising features including specific and reversible target binding and inhibition. Aptamers can function as anticoagulants if they are directed against enzymes of the coagulation cascade. However, they typically suffer from nucleolytic digestion and fast clearance from the bloodstream. We present thrombin binding aptamer amphiphiles that self-assemble into nanoscale polymeric micelles with a densely functionalized aptamer-displaying corona. We show that these micellar aptamers retain their native secondary structure in a crowded environment and are stabilized against degradation by nucleases in human serum. Moreover, they are effective inhibitors of human plasma clotting in vitro. The inhibitory effect can be rapidly reversed by complementary nucleic acids that break the aptamers' secondary structure upon hybridization. Compared to free aptamers, the increased molecular weight and size of the overall assembly promotes extended blood circulation times in vivo.