Wei Yun, Chen Peiru, Ren Mengqi, Li Deng, Lin Jiachen, Sun Tingyu, Wang Yuyan, Yang Shaobo, Nenopoulos Christopher, Oetheimer Christopher, Li Yao, Xue Chenyang, Minkara Mona, Zhang Ke
Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, United States.
Department of Bioengineering, Northeastern University, Boston, Massachusetts 02115, United States.
J Am Chem Soc. 2024 Dec 18;146(50):34763-34770. doi: 10.1021/jacs.4c13285. Epub 2024 Nov 27.
The clinical translation of oligonucleotide-based therapeutics continues to encounter challenges in delivery. In this study, we introduce a novel class of delivery vehicles for oligonucleotides that are based on poly(ethylene glycol) (PEG) bottlebrush polymers with sequence-defined backbones. Using solid-phase synthesis and bespoke phosphoramidites, the oligonucleotide and the polymer backbone can be assembled on the solid support. The synthesis allows chemical modifiers such as carbon 18 (C) units to be incorporated into the backbone in specific patterns to modulate the cell-material interactions. Subsequently, PEG side chains were grafted onto the polymer segment of the resulting polymer-oligonucleotide conjugate, yielding bottlebrush polymers. We report an optimal pattern of the C modifier that leads to improved cellular uptake, plasma pharmacokinetics, biodistribution, and antisense activity . Our results provide valuable insights into the structure-property relationship of polymer-oligonucleotide conjugates and suggest the possibility of tuning the polymer backbone to meet the specific delivery requirements of various diseases.
基于寡核苷酸的治疗药物的临床转化在递送方面仍面临挑战。在本研究中，我们引入了一类新型的寡核苷酸递送载体，其基于具有序列定义主链的聚乙二醇（PEG）刷状聚合物。使用固相合成和定制亚磷酰胺，可以在固体支持物上组装寡核苷酸和聚合物主链。该合成允许将化学修饰剂（如碳18（C）单元）以特定模式掺入主链中，以调节细胞与材料的相互作用。随后，将PEG侧链接枝到所得聚合物-寡核苷酸缀合物的聚合物链段上，得到刷状聚合物。我们报告了一种C修饰剂的最佳模式，该模式可导致细胞摄取、血浆药代动力学、生物分布和反义活性得到改善。我们的结果为聚合物-寡核苷酸缀合物的结构-性质关系提供了有价值的见解，并表明了调整聚合物主链以满足各种疾病特定递送要求的可能性。
