Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA.
Department of Bioengineering, Northeastern University, Boston, MA 02115, USA.
Angew Chem Int Ed Engl. 2022 Oct 10;61(41):e202204576. doi: 10.1002/anie.202204576. Epub 2022 Sep 6.
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.
适体在其开发的理想条件之外的应用面临挑战。由于核酸酶活性、快速清除和非特异性结合，这些困难在体内最为明显。在此，我们证明了一种聚磷酸二酯骨架的分子刷可以抑制酶解、减少非特异性细胞摄取、实现长血液循环，并在体内恢复共轭适体的生物活性。骨架与适体通过固相合成组装，然后使用两步法以近乎定量的效率安装聚（乙二醇）（PEG）侧链。该合成允许对聚合物尺寸和结构进行精确控制。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，有望为基于适体的治疗提供一种高度可转化的途径。
