Key Laboratory of Drug Targeting and Drug Delivery System (Ministry of Education), West China School of Pharmacy, Sichuan University, No. 17, Block 3, South Renmin Road, Chengdu 610041, PR China.
Key Laboratory of Drug Targeting and Drug Delivery System (Ministry of Education), West China School of Pharmacy, Sichuan University, No. 17, Block 3, South Renmin Road, Chengdu 610041, PR China.
Int J Pharm. 2020 Apr 30;580:119224. doi: 10.1016/j.ijpharm.2020.119224. Epub 2020 Mar 12.
Nucleus is the central regulator of cell metabolism, growth and differentiation, which is considered as an effective target for the treatment of many diseases. To efficiently deliver drugs into nucleus, delivery systems have to bypass a number of barriers especially crossing the cell membrane and nuclear envelope. Here we report a nucleolar targeting peptide (NrTP6) modified polymeric conjugate platform based on N-(2-hydroxypropyl)-methacrylamide (HPMA) copolymers for enhanced nuclear delivery of H1-S6A, F8A peptide to hinder c-Myc from binding to DNA. On one hand, the modification of NrTP6 would promote cellular uptake and nuclear accumulation of the conjugates, and on the other hand, the conjugates can release smaller molecular weight subunits (H1-NrTP6) via cleavage of lysosomally enzyme-sensitive spacer for facilitating nucleus transport. It was found that NrTP6 modified HPMA copolymer-H1 peptide conjugates could improve internalization and nuclear accumulation of H1 peptide by 2.2 and 37.1-fold, respectively, compared to the non-NrTP6 modified ones, in HeLa cells. Moreover, the same trend was found in MDA-MB-231 cells and 4T1 cells. In addition, we found that the nuclear targeting mechanism of NrTP6 peptide mediation may be associated with the importin α/β pathway. Furthermore, the in vivo investigation revealed that NrTP6-modified polymeric platform exhibited the best therapeutic efficacy with a tumor growth inhibition rate of 77.0%. These results indicated that NrTP6 modification was a promising strategy for simultaneously realizing cellular internalization and nuclear targeting, which might provide a new path for intranuclear drug delivery.
核是细胞代谢、生长和分化的中央调控者，被认为是治疗许多疾病的有效靶点。为了将药物有效地递送到核内，递药系统必须克服许多障碍，特别是穿过细胞膜和核膜。在这里，我们报告了一种基于 N-(2-羟丙基)甲基丙烯酰胺 (HPMA) 共聚物的核仁靶向肽 (NrTP6) 修饰的聚合物缀合物平台，用于增强 H1-S6A、F8A 肽的核内递送，以阻止 c-Myc 与 DNA 结合。一方面，NrTP6 的修饰将促进细胞摄取和缀合物的核积累，另一方面，缀合物可以通过裂解溶酶体酶敏感间隔释放更小分子量的亚单位 (H1-NrTP6)，以促进核转运。研究发现，与非 NrTP6 修饰的缀合物相比，NrTP6 修饰的 HPMA 共聚物-H1 肽缀合物可以分别将 H1 肽的内化和核积累提高 2.2 和 37.1 倍，在 HeLa 细胞中。此外，在 MDA-MB-231 细胞和 4T1 细胞中也发现了相同的趋势。此外，我们发现 NrTP6 肽介导的核靶向机制可能与导入蛋白 α/β 途径有关。此外，体内研究表明，NrTP6 修饰的聚合物平台表现出最佳的治疗效果，肿瘤生长抑制率为 77.0%。这些结果表明，NrTP6 修饰是一种同时实现细胞内吞和核靶向的有前途的策略，可能为核内药物递送提供新途径。
