He Xiao, Qu Yannv, Xiong Su, Jiang Zhiru, Tang Yaqin, Yan Fei, Deng Yuanfei, Sun Yansun
Department of Geriatrics, Peking University Shenzhen Hospital, Shenzhen 518036, China.
Center for Cell and Gene Circuit Design, CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
J Funct Biomater. 2023 May 30;14(6):301. doi: 10.3390/jfb14060301.
The utilization of cytosolic protein delivery is a promising approach for treating various diseases by replacing dysfunctional proteins. Despite the development of various nanoparticle-based intracellular protein delivery methods, the complicated chemical synthesis of the vector, loading efficiency and endosomal escape efficiency of proteins remain a great challenge. Recently, 9-fluorenylmethyloxycarbonyl (Fmoc)-modified amino acid derivatives have been used to self-assemble into supramolecular nanomaterials for drug delivery. However, the instability of the Fmoc group in aqueous medium restricts its application. To address this issue, the Fmoc ligand neighboring arginine was substituted for dibenzocyclooctyne (DBCO) with a similar structure to Fmoc to obtain stable DBCO-functionalized L-arginine derivative (DR). Azide-modified triethylamine (crosslinker C) was combined with DR to construct self-assembled DRC via a click chemical reaction for delivering various proteins, such as BSA and saporin (SA), into the cytosol of cells. The hyaluronic-acid-coated DRC/SA was able to not only shield the cationic toxicity, but also enhance the intracellular delivery efficiency of proteins by targeting CD44 overexpression on the cell membrane. The DRC/SA/HA exhibited higher growth inhibition efficiency and lower IC compared to DRC/SA toward various cancer cell lines. In conclusion, DBCO-functionalized L-arginine derivative represents an excellent potential vector for protein-based cancer therapy.
通过替换功能失调的蛋白质来利用胞质蛋白递送是一种治疗各种疾病的有前景的方法。尽管基于纳米颗粒的细胞内蛋白质递送方法有了发展，但载体复杂的化学合成、蛋白质的负载效率和内体逃逸效率仍然是巨大的挑战。最近，9-芴甲氧羰基（Fmoc）修饰的氨基酸衍生物已被用于自组装成用于药物递送的超分子纳米材料。然而，Fmoc基团在水性介质中的不稳定性限制了其应用。为了解决这个问题，将与精氨酸相邻的Fmoc配体替换为与Fmoc结构相似的二苯并环辛炔（DBCO），以获得稳定的DBCO功能化L-精氨酸衍生物（DR）。叠氮化物修饰的三乙胺（交联剂C）与DR结合，通过点击化学反应构建自组装的DRC，用于将各种蛋白质，如牛血清白蛋白（BSA）和皂草素（SA）递送至细胞胞质溶胶中。透明质酸包被DRC/SA不仅能够屏蔽阳离子毒性，还能通过靶向细胞膜上CD44的过表达提高蛋白质的细胞内递送效率。与DRC/SA相比，DRC/SA/HA对各种癌细胞系表现出更高的生长抑制效率和更低半数抑制浓度（IC）。总之，DBCO功能化L-精氨酸衍生物是基于蛋白质的癌症治疗的一种极具潜力的载体。
