A Long-Circulating Vector for Aptamers Based upon Polyphosphodiester-Backboned Molecular Brushes.
A Long-Circulating Vector for Aptamers Based upon Polyphosphodiester-Backboned Molecular Brushes.
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基于聚磷酸二酯的分子刷，用于适体的长循环载体。
DOI：
10.1002/anie.202204576
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发表时间：
2022-10-10
影响因子：
16.6
通讯作者：
Zhang, Ke
中科院分区：
文献类型：
--
作者：
Wang, Yuyan;Wang, Dali;Lin, Jiachen;Lyu, Zidi;Chen, Peiru;Sun, Tingyu;Xue, Chenyang;Mojtabavi, Mehrnaz;Vedadghavami, Armin;Zhang, Zheyu;Wang, Ruimeng;Zhang, Lei;Park, Christopher;Heo, Gyu Seong;Liu, Yongjian;Dong, Sijia;Zhang, Ke
适体在其开发的理想条件之外的使用面临挑战。由于核酸酶活性、快速清除和脱靶结合，这些困难在体内最为明显。在此，我们证明了多磷酸二酯骨架分子刷可以抑制酶消化，减少非特异性细胞摄取，促进长血液循环，并在体内恢复共轭适体的生物活性。主链和适配体通过固相合成进行组装，然后使用两步工艺安装聚乙二醇（PEG）侧链，具有接近定量的效率。这种合成方法可以精确控制聚合物的尺寸和结构。这种新型分子刷完全由通常被认为对治疗安全的构建块组成，有望为基于适配体的治疗提供高度可翻译的途径。一个瓶刷聚合物-适体生物杂交体，称为PSP pacDNA，是用固相和接枝方法制备的。PSP pacDNA由聚磷酸二酯主链和聚乙二醇侧链组成，可抑制与细胞的非特异性相互作用，并改善适体的血浆药代动力学。结合凝血酶结合适体，PSP pacDNA在体内产生明显的抗凝作用。
Aptamers face challenges for use outside the ideal conditions in which they are developed. These difficulties are most palpable in vivo due to nuclease activities, rapid clearance, and off-target binding. Herein, we demonstrate that a polyphosphodiester-backboned molecular brush can suppress enzymatic digestion, reduce non-specific cell uptake, enable long blood circulation, and rescue the bioactivity of a conjugated aptamer in vivo. The backbone along with the aptamer is assembled via solid-phase synthesis, followed by installation of poly(ethylene glycol) (PEG) side chains using a two-step process with near-quantitative efficiency. The synthesis allows for precise control over polymer size and architecture. Consisting entirely of building blocks that are generally recognized as safe for therapeutics, this novel molecular brush is expected to provide a highly translatable route for aptamer-based therapeutics. A bottlebrush polymer-aptamer biohybrid, termed PSP pacDNA, is prepared using solid-phase and graft-onto methodologies. Consisting of a polyphosphodiester backbone and poly(ethylene glycol) side chains, the PSP pacDNA suppresses non-specific interactions with the cell and improves the plasma pharmacokinetics of the aptamer. Combined with a thrombin-binding aptamer, the PSP pacDNA produces a pronounced anticoagulation effect in vivo.
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影响因子：
8.4
作者：
Hong S;Zhang X;Lake RJ;Pawel GT;Guo Z;Pei R;Lu Y
通讯作者：
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影响因子：
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作者：
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Bockstaller, MR
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通讯作者：
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作者：
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通讯作者：
SZOSTAK, JW