Li Fan, Xu Xing, Liang Yan, Li Yan, Wang Miaochen, Zhao Fen, Wang Xu, Sun Yong, Chen Wantao
Department of Oral and Maxillofacial Head & Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
Department of Pharmaceutics, Qingdao University School of Pharmacy, Qingdao, 266021, China.
Nanoscale. 2021 Mar 12;13(9):4774-4784. doi: 10.1039/d0nr07239g.
GNA002, a novel EZH2 inhibitor, exhibits significant anticancer efficiency in solid malignant tumor therapy; however, its poor water solubility and low enrichment at tumor sites limit its clinical application and translation. In this study, an original pH-sensitive nanocarrier (cyclo (RGDyCSH) (cRGD)-poly (ethylene glycol) (PEG)-hydrazine (Hyd)-hexa-arginine (R6)-stearic acid (SA)) was designed to precisely deliver GNA002 into the nuclei of cancer cells. The PEG-modified hydrophilic shell of the spherical GNA002-loaded nanoparticles with a mean size of 143.13 ± 0.20 nm effectively facilitated the passive target of tumor tissues and prolonged the blood circulation time. Meanwhile, cRGD was used as the active targeting ligand, which promoted the accumulation of the nanoparticles in cancer cells via ανβ3-receptor-mediated endocytosis. Furthermore, the acidic environment of lysosomes triggered the rupture of the pH-sensitive hydrazine bond and the rapid formation of penetrating peptide R6-shelled secondary nanoparticles, thus enabling the lysosomal escape of the nanoparticles and the ultimate R6-mediated nuclear-targeted delivery of GNA002. Consequently, the nuclear-enriched GNA002 effectively enhanced the cytotoxicity against cancer cells both in vitro and in vivo, thus providing an original and promising drug delivery system for the targeted delivery of GNA002.
新型EZH2抑制剂GNA002在实体恶性肿瘤治疗中展现出显著的抗癌效果；然而，其较差的水溶性以及在肿瘤部位的低富集性限制了它的临床应用和转化。在本研究中，设计了一种新型的pH敏感纳米载体（环（RGDyCSH）（cRGD）-聚乙二醇（PEG）-肼（Hyd）-六聚精氨酸（R6）-硬脂酸（SA）），以将GNA002精准递送至癌细胞核内。平均粒径为143.13±0.20 nm的负载GNA002的球形纳米颗粒的PEG修饰亲水外壳有效地促进了肿瘤组织的被动靶向并延长了血液循环时间。同时，cRGD用作主动靶向配体，通过ανβ3受体介导的内吞作用促进纳米颗粒在癌细胞中的积累。此外，溶酶体的酸性环境触发了pH敏感肼键的断裂以及穿透肽R6包裹的次级纳米颗粒的快速形成，从而使纳米颗粒能够从溶酶体逃逸，并最终实现R6介导的GNA002核靶向递送。因此，核富集的GNA002在体外和体内均有效增强了对癌细胞的细胞毒性，从而为GNA002的靶向递送提供了一种新颖且有前景的药物递送系统。
